Pyrrolo[3,2-]pyrimidine derivatives for the treatment of viral infections and other diseases

ABSTRACT

This invention concerns pyrrolo[3,2-d]pyrimidine derivatives, processes for their preparation, pharmaceutical compositions, and their use in treatment and/or therapy of diseases.

This application is a 35 U.S.C. 371 nationalization of PCT applicationPCT/EP2013/070990 filed Oct. 9, 2013, which claims priority to Europeanpatent application EP12187994.4 filed Oct. 10, 2012, both of which areincorporated herein by reference.

This invention relates to pyrrolo[3,2-d]pyrimidine derivatives,processes for their preparation, pharmaceutical compositions, and theiruse in treatment and/or therapy of diseases.

The present invention relates to the use of pyrrolo-pyrimidinederivatives, more specifically to the use of pyrrolo[3,2-d]pyrimidinederivatives in the treatment of viral infections, immune or inflammatorydisorders, whereby the modulation, or agonism, of toll-like-receptors(TLRs) is involved. Toll-Like Receptors are primary transmembraneproteins characterized by an extracellular leucine rich domain and acytoplasmic extension that contains a conserved region. The innateimmune system can recognize pathogen-associated molecular patterns viathese TLRs expressed on the cell surface of certain types of immunecells. Recognition of foreign pathogens activates the production ofcytokines and upregulation of co-stimulatory molecules on phagocytes.This leads to the modulation of T cell behaviour.

A majority of mammalian species have between ten and fifteen types ofToll-like receptors. Thirteen TLRs (named simply TLR1 to TLR13) havebeen identified in humans and mice together, and equivalent forms ofmany of these have been found in other mammalian species. However,equivalents of certain TLR found in humans are not present in allmammals. For example, a gene coding for a protein analogous to TLR10 inhumans is present in mice, but appears to have been damaged at somepoint in the past by a retrovirus. On the other hand, mice express TLRs11, 12, and 13, none of which are represented in humans. Other mammalsmay express TLRs which are not found in humans. Other non-mammalianspecies may have TLRs distinct from mammals, as demonstrated by TLR14,which is found in the Takifugu pufferfish. This may complicate theprocess of using experimental animals as models of human innateimmunity.

For reviews on toll-like receptors see the following journal articles.Hoffmann, J. A., Nature, 426, p 33-38, 2003; Akira, S., Takeda, K., andKaisho, T., Annual Rev. Immunology, 21, p 335-376, 2003; Ulevitch, R.J., Nature Reviews: Immunology, 4, p 512-520, 2004.

Compounds indicating activity on Toll-Like receptors have beenpreviously described such as heterocyclic derivatives in WO2000006577,adenine derivatives in WO 98/01448 and WO 99/28321, and pyrimidines inWO 2009/067081.

In the treatment of certain viral infections, regular injections ofinterferon (IFN-alfa) can be administered, as is the case for hepatitisC virus (HCV) (Fried et. al. Peginterferon-alfa plus ribavirin forchronic hepatitis C virus infection, N Engl J Med 2002; 347: 975-82).Orally available small molecule IFN inducers offer the potentialadvantages of reduced immunogenicity and convenience of administration.Thus, novel IFN inducers are potentially effective new class of drugsfor treating virus infections. For an example in the literature of asmall molecule IFN inducer having antiviral effect see De Clercq, E.;Descamps, J.; De Somer, P. Science 1978, 200, 563-565.

Interferon alpha is also given to patients in combination with otherdrugs in the treatment of certain types of cancer (Eur. J. Cancer (46) p2849-57, and Cancer Res. 1992 (52) p. 1056). TLR 7/8 agonists are alsoof interest as vaccine adjuvants because of their ability to inducepronounced Th1 response (Hum. Vaccines, 2009 (5), 381-394).

However, there exists a strong need for novel Toll-Like receptormodulators having preferred selectivity, and an improved safety profilecompared to the compounds of the prior art.

In accordance with the present invention a compound of formula (I) isprovided

and their pharmaceutically acceptable salt, solvate prodrug,stereoisomers or polymorph thereof whereinR₁ is H, fluorine or methyl;R₂ is H, halogen or C₁₋₃ alkyl;R₃ is C₁₋₆ alkyl optionally substituted by aryl optionally furthersubstituted by one or more substituents independently selected fromaryloxy, halogen, aryl, alkylamino, dialkylamino, heterocycloalkyl, C₁₋₆cycloalkyl, C₁₋₆ alkyl, carboxylic acid, carboxylic ester, carboxylicamide, nitrile, or C₁₋₆ alkoxy; orR₃ is C₁₋₆ alkyl optionally substituted by C₁₋₆ alkene, C₃₋₇ cycloalkylor C₃₋₇ heterocycloalkyl; orR₃ is C₁₋₆ alkyl optionally substituted by C₁₋₆ alkoxy optionallyfurther substituted by aryl;R₄ is C₁₋₈ alkyl optionally substituted by one or more substituentsindependently selected from hydroxyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₂₋₆ alkenyl, aryl, heteroaryl optionally furthersubstituted by C₁₋₆ alkyl, and C₃₋₇ cycloalkyl optionally furthersubstituted by C₁₋₆ alkyl;with the proviso that2-amino-4-(N-butylamino)-5-(alphamethylbenzyl)pyrrolo[3,2-d]pyrimidineis excluded.

Preferred compounds are those of formula (I) wherein R₃ is a C₁₋₃ alkylgroup substituted with an aryl (substituted or unsubstituted), and R₁,R₂, and R₄ are described as above.

In a second embodiment are the compounds of formula (I) wherein R₃ andR₄ are a C₁₋₃ alkyl substituted by an aryl, optionally furthersubstituted as described above.

In a further embodiments are those of formula (I) wherein R₁ ishydrogen, R₂ is fluorine, and R₃ and R₄ are described as above.

Other preferred embodiments are those of formula (I) wherein R₁ isfluorine, R₂ is hydrogen, and R₃ and R₄ are described as above.

The compounds, as listed in Tables I and II, having the followingnumbers #89, 94, 101, 144, 154, 156, 175, 192, 209, 213 and 215 are ofspecial interest because of their properties according to the inventiondisclosed herein.

The compounds of formula (I) and their pharmaceutically acceptable salt,solvate or polymorph thereof have activity as pharmaceuticals, inparticular as modulators of Toll-Like Receptor (especially TLR7 and/orTLR8) activity.

In a further aspect the present invention provides a pharmaceuticalcomposition comprising a compound of formula (I) or a pharmaceuticallyacceptable salt, solvate or polymorph thereof together with one or morepharmaceutically acceptable excipients, diluents or carriers.

Furthermore a compound of formula (I) or a pharmaceutically acceptablesalt, solvate or polymorph thereof according to the current invention,or a pharmaceutical composition comprising said compound of formula (I)or a pharmaceutically acceptable salt, solvate or polymorph thereof canbe used as a medicament.

Another aspect of the invention is that a compound of formula (I) or apharmaceutically acceptable salt, solvate or polymorph thereof, or saidpharmaceutical composition comprising said compound of formula (I) or apharmaceutically acceptable salt, solvate or polymorph thereof can beused accordingly in the treatment of any disorder in which themodulation of TLR7 and/or TLR8 is involved.

The term “alkyl” refers to a straight-chain or branched-chain saturatedaliphatic hydrocarbon containing the specified number of carbon atoms.

The term “halogen” refers to fluorine, chlorine, bromine or iodine.

The term “alkenyl” refers to an alkyl as defined above consisting of atleast two carbon atoms and at least one carbon-carbon double bond.

The term “cycloalkyl” refers to a carbocyclic ring containing thespecified number of carbon atoms.

The term “alkoxy” refers to an alkyl (carbon and hydrogen chain) groupsingular bonded to oxygen like for instance a methoxy group or ethoxygroup.

The term “aryl” means an aromatic ring structure optionally comprisingone or two heteroatoms selected from N, O and S, in particular from Nand O. Said aromatic ring structure may have 5, 6 or 7 ring atoms. Inparticular, said aromatic ring structure may have 5 or 6 ring atoms.Said aromatic ring structure may also be fused to another aryl ringaffording a bicyclic structure (examples include but are not limited to:quinoline, isoquinoline, quinazoline, benzoxazole).

The term “aryloxy” refers to an aromatic ring structure. Said aromaticgroup is singularly bonded to oxygen (e.g. phenoxy).

The term “alkene” refers to an unsaturated hydrocarbon chain containingthe specified number of carbon atoms containing at least one carbon-tocarbon double bond.

The term “heterocycle” refers to molecules that are saturated orpartially saturated and include tetrahydrofuran, dioxane or other cyclicethers. Heterocycles containing nitrogen include, for example azetidine,morpholine, piperidine, piperazine, pyrrolidine, and the like. Otherheterocycles include, for example, thiomorpholine, dioxolinyl, andcyclic sulfones.

Pharmaceutically acceptable salts of the compounds of formula (I)include the acid addition and base salts thereof. Suitable acid additionsalts are formed from acids which form non-toxic salts. Suitable basesalts are formed from bases which form non-toxic salts.

The compounds of the invention may also exist in unsolvated and solvatedforms. The term “solvate” is used herein to describe a molecular complexcomprising the compound of the invention and one or morepharmaceutically acceptable solvent molecules, for example, ethanol.

The term “polymorph” refers to the ability of the compound of theinvention to exist in more than one form or crystal structure.

The compounds of the present invention may be administered ascrystalline or amorphous products. They may be obtained for example assolid plugs, powders, or films by methods such as precipitation,crystallization, freeze drying, spray drying, or evaporative drying.They may be administered alone or in combination with one or more othercompounds of the invention or in combination with one or more otherdrugs. Generally, they will be administered as a formulation inassociation with one or more pharmaceutically acceptable excipients. Theterm “excipient” is used herein to describe any ingredient other thanthe compound(s) of the invention. The choice of excipient dependslargely on factors such as the particular mode of administration, theeffect of the excipient on solubility and stability, and the nature ofthe dosage form.

The compounds of the present invention or any subgroup thereof may beformulated into various pharmaceutical forms for administrationpurposes. As appropriate compositions there may be cited allcompositions usually employed for systemically administering drugs. Toprepare the pharmaceutical compositions of this invention, an effectiveamount of the particular compound, optionally in addition salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, for example, for oral, rectal, orpercutaneous administration. For example, in preparing the compositionsin oral dosage form, any of the usual pharmaceutical media may beemployed such as, for example, water, glycols, oils, alcohols and thelike in the case of oral liquid preparations such as suspensions,syrups, elixirs, emulsions, and solutions; or solid carriers such asstarches, sugars, kaolin, diluents, lubricants, binders, disintegratingagents and the like in the case of powders, pills, capsules, andtablets. Because of their ease in administration, tablets and capsulesrepresent the most advantageous oral dosage unit forms, in which casesolid pharmaceutical carriers are obviously employed. Also included aresolid form preparations that can be converted, shortly before use, toliquid forms. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notintroduce a significant deleterious effect on the skin. Said additivesmay facilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment. The compounds of the present invention may alsobe administered via inhalation or insufflation by means of methods andformulations employed in the art for administration via this way. Thus,in general the compounds of the present invention may be administered tothe lungs in the form of a solution, a suspension or a dry powder.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

Those of skill in the treatment of infectious diseases will be able todetermine the effective amount from the test results presentedhereinafter. In general it is contemplated that an effective dailyamount would be from 0.01 mg/kg to 50 mg/kg body weight, more preferablyfrom 0.1 mg/kg to 10 mg/kg body weight. It may be appropriate toadminister the required dose as two, three, four or more sub-doses atappropriate intervals throughout the day. Said sub-doses may beformulated as unit dosage forms, for example, containing 1 to 1000 mg,and in particular 5 to 200 mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weightand general physical condition of the particular patient as well asother medication the individual may be taking, as is well known to thoseskilled in the art. Furthermore, it is evident that the effective amountmay be lowered or increased depending on the response of the treatedsubject and/or depending on the evaluation of the physician prescribingthe compounds of the instant invention. The effective amount rangesmentioned above are therefore only guidelines and are not intended tolimit the scope or use of the invention to any extent.

EXPERIMENTAL SECTION

Compounds of type A in scheme 1 can be alkylated with benzyl bromidesusing a polar aprotic solvent, for example DMF. The reaction of alkylhalides with intermediate A requires a stronger base (e.g. cesiumcarbonate) and possibly a longer reaction time and/or increasedtemperature. The displacement of the chlorine in intermediate B with anamine to form compounds of the type C may require additional heating orprolonged reaction time as observed with aminoalcohols (for thepreparation of aminoalcohols refer to WO2009067081 and WO2008147697).The displacement of the chlorine in intermediate B with an amine mayalso proceed at room temperature in a polar solvent (e.g. DMF oracetonitrile). A variety of bases may be used to aid in the reactionfrom B to C including but not limited to the following: triethylamine,diisopropylamine, cesium carbonate, potassium carbonate, or sodiumhydride. The reduction of the azido group in compounds represented bythe intermediate D above may also proceed over Pd/C in a hydrogenatmosphere. Intermediates B, C, and D containing fluorine can besubstituted under the same protocols as the unsubstituted analogs, thus,reaction schemes described apply to both types of compounds.

Preparation of Intermediate B

Into a 50 mL vial was placed 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine[CAS 63200-54-4] (1 g, 5.319 mmol), DMF (10 mL), DIPEA (2.75 mL, 16mmol) and benzyl bromide (0.7 mL, 5.85 mmol). The vial was sealed andshaken for 16 hours at room temperature. The solvents were removed underreduced pressure. The crude was purified via silica gel columnchromatography using a heptane to ethyl acetate gradient. The bestfractions were pooled and the solvents were removed under reducedpressure to afford B.

LC-MS (M+H) m/z=278

Preparation of Intermediate B2

Into a 50 mL vial equipped with a magnetic stir bar was placed A (50 mg,0.27 mmol), anhydrous DMF (1 mL), cesium carbonate (0.259 g, 0.8 mmol)and then 2-bromoethyl methyl ether (0.03 mL, 0.29 mmol). The flask wassealed, and the reaction was allowed to stir at 70° C. for 2 hours. Thesolvents were removed under reduced pressure. The crude was purified viasilica gel column chromatography using a heptane to ethyl acetategradient. The best fractions were pooled and the solvents were removedunder reduced pressure to afford B2.

LC-MS (M+H) m/z=246

Preparation of Intermediate C

Into a 50 mL round bottom flask equipped with a magnetic stir bar wasplaced B (1.4 g, 5.03 mmol), n-butylamine (0.59 mL, 6.04 mmol), and1,4-dioxane (5 mL). The flask was equipped with a reflux condenser andallowed to heat with stirring at 100° C. for 16 hours. After cooling toroom temperature, the solvents were removed under reduced pressure. Thecrude was purified via silica gel column chromatography using a heptaneto ethyl acetate gradient. The best fractions were pooled and thesolvents were removed under reduced pressure to afford C.

LC-MS (M+H) m/z=315

Preparation of Intermediate D

Into a glass vial equipped with a magnetic stir bar was placed C (1 g,3.18 mmol), sodium azide (0.62 g, 9.53 mmol), and NMP:water (9:1, 4 mL).The glass vial was sealed and the mixture was heated with stirring to170° C. for 5 hours. After cooling to room temperature, the mixture wasdiluted with ethyl acetate (20 mL) and washed with water (5×15 mL). Theorganic layer was dried over magnesium sulfate, the solids were removedvia filtration and the solvents of the filtrate were removed underreduced pressure. The crude was purified via silica gel columnchromatography using a heptane to ethyl acetate gradient. The bestfractions were combined and the solvents were removed under reducedpressure to afford D.

LC-MS (M+H) m/z=322

Preparation of 1

Into a glass vial equipped with a magnetic stir bar was placed D (100mg, 0.311 mmol), 1,4-dioxane (4 mL), water (1 mL), andtriphenylphosphine (245 mg, 0.93 mmol). The glass vial was sealed andthe mixture heated with stirring to 120° C. for 48 hours. After coolingto room temperature, the solvents were removed under reduced pressure.The crude was purified via silica gel column chromatography using adichloromethane to 10% methanol in dichloromethane gradient. The bestfractions were pooled and the solvents were removed under reducedpressure to afford 1.

LC-MS (M+H) m/z=296

Preparation of 86

Into a glass vial equipped with a magnetic stir bar was placed 1 (110mg, 0.372 mmol), nitromethane (1.5 mL), and selectfluor (198 mg, 0.56mmol). The glass vial was sealed and the mixture stirred at roomtemperature for 16 hours. The solvents were removed under reducedpressure. The crude was purified via reverse phase chromatography. Thebest fractions were pooled and the solvents were removed under reducedpressure to afford 86.

Preparation of Intermediate E

Into a glass vial equipped with a magnetic stir bar was placed A (600mg, 3.19 mmol), nitromethane (10 mL), and selectfluor (5.67 g, 16 mmol).The glass vial was sealed and the mixture stirred at room temperaturefor 48 hours. NaHCO₃ (sat. aq., 10 mL) was added and extracted withethyl acetate (3×15 mL). The organic layers were pooled, dried overmagnesium sulfate, the solids were removed by filtration, and thesolvent of the filtrate was removed under reduced pressure to affordcrude E, used as such in the next step.

LC-MS (M+H) m/z=206

Preparation of intermediate G

Step 1

Intermediate F was prepared according to the method used to preparecompound 9 in scheme 3 on page 44 of WO2010006025. With the exceptionthat acetyl group was employed in place of the trimethylacetyl group.

Step 2. Preparation of Intermediate G

Into a 50 mL glass vial equipped with a magnetic stir bar was placed F(200 mg, 0.97 mmol), anhydrous DMF (5 mL), DBU (0.435 mL, 2.91 mmol),and BOP (536 mg, 1.2 mmol). The reaction mixture becomes a solutionafter stirring for several minutes, then n-butylamine (0.48 mL, 4.85mmol) was added and the stirring continues at room temperature for 16hours. The solvent was removed under reduced pressure and the crude waspurified via reverse phase chromatography.

LC-MS (M+H) m/z=262

General procedure. Compounds of type X in scheme 2 can be functionalizedwith alcohols using Mitsunobu conditions in a polar aprotic solvent, forexample THF. Cleavage of methyl carbamate was performed under basicconditions in 1,4-dioxane to form intermediate Z. The displacement ofthe chlorine in intermediate Z was performed with an amine and a base(e.g. NaH) in a polar solvent (e.g. NMP) to form compounds of formula(I).

Preparation of Intermediate X

3-Amino-2-ethoxycarbonylpyrrole hydrochloride (25.8 g, 135.3 mmol) waspartitioned between dichloromethane and sat. NaHCO₃, dried over MgSO₄,filtered and evaporated to dryness. The residue was dissolved inmethanol (500 mL) together with1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (32.1 g, 156 mmol)and acetic acid (39 mL, 677 mmol) and stirred 1 hour at roomtemperature. A precipitate appeared and stirring was continuedovernight. Sodium methoxide (73.1 g, 1353 mmol) was added. An exothermwas observed and the reaction mixture was stirred overnight. Thereaction mixture was brought to pH 5 via addition of acetic acid and theprecipitate was filtered off, triturated with water (2×350 mL),acetonitrile (1×350 mL) and diisopropylether (1×350 mL). The obtainedmethyl N-(4-hydroxy-5H-pyrrolo[3,2-d]pyrimidin-2-yl)carbamate was driedin the oven.

Methyl N-(4-hydroxy-5H-pyrrolo[3,2-d]pyrimidin-2-yl)carbamate (25 g, 120mmol) was dispensed into acetonitrile (350 mL) in a 500 mL multi neckflask at room temperature. POCl₃ (22.1 mL, 238.2 mmol) was added and thereaction mixture was heated to 70° C. while stirring by an overhead,mechanical stirrer (300 rpm). Hunig's base (41.4 mL, 240.2 mmol) wasadded dropwise via a syringe pump at a flow rate of 0.2 mL/min. Thereaction mixture was cooled to room temperature and poured into astirred solution of sodium acetate (78.8 g, 961 mmol) in water (500 mL)at 45° C. The organics were evaporated and the remaining liquid wasstirred and cooled in an ice bath. The formed solid was isolated byfiltration, washed with acetonitrile and triturated withdiisopropylether to become intermediate X as a solid which was driedunder vacuum.

Preparation of Intermediate Y

To a suspension of intermediate X (5 g, 22 mmol), 2-pyridinemethanol(2.6 mL, 26.5 mmol) and polystyrene-bound triphenylphosphine (18.4 g,55.2 mmol) in anhydrous THF (153 mL) was added DIAD (6.9 mL, 33 mmol) atroom temperature and the reaction mixture stirred for 30 minutes thenwas concentrated under reduced pressure. The product was purified viasilica gel column chromatography using gradient adichloromethane:methanol 100:0 to 90:10 gradient. The product fractionswere collected and concentrated under reduced pressure. The product wasrecrystallized in acetonitrile, isolated by filtration and dried undervacuum to afford Y as a white solid.

Preparation of Intermediate Z

Y (4.5 g, 14.2 mmol) was dissolved in 1,4-dioxane (68 mL) in a 100 mLround bottom flask and 1 N NaOH (34 mL) was added. The mixture washeated to 60° C. for 5 h. The mixture was cooled and concentrated underreduced pressure. The residue was treated with water and the precipitatewas isolated by filtration and dried to afford Z. The product was usedas such in the next step.

Z (175 mg, 0.67 mmol), isoxazol-3-yl-methylamine hydrochloride (136 mg,1.0 mmol), and diisopropylethylamine (173 mg, 1.3 mmol) were dissolvedin NMP (2.4 mL) in a 7 mL glass vial. The mixture was stirred at 100° C.for 2 h then cooled and concentrated in vacuo. It was purified by PrepHPLC (Stationary phase: RP Vydac Denali C18—10 μm, 200 g, 5 cm), Mobilephase: 0.25% NH₄OAc solution in water, methanol), the desired fractionswere collected and concentrated in vacuo. The product was triturated inacetonitrile, isolated by filtration and dried under vacuum to become155 as a white solid.

TABLE 1 Compounds of formula (I) and corresponding analytical data. LCMethod, LC-MS Mass # STRUCTURE ¹H NMR Rt (min) Found  1

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.77 (t, J = 7.3 Hz, 3 H), 0.98-1.11 (m,2 H), 1.33 (dt, J = 14.5, 7.2 Hz, 2 H), 3.25-3.30 (m, 2 H), 5.23 (s, 2H), 5.48 (s, 6 2 H), 5.75 (t, J = 5.5 Hz, 1 H), 5.98 (d, J = 3.0 Hz, 1H), 6.97 (d, J = 7.0 Hz, 2 H), 7.19-7.35 (m, 4 H) B, 0.88 296  2

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.76 (t, J = 7.2 Hz, 3 H), 1.07(dq, J = 14.9, 7.3 Hz, 2 H), 1.23-1.35 (m, 2 H), 3.31 (td, J = 6.8, 5.6Hz, 2 H), 4.90 (t, J = 4.9 Hz, 1 H), 5.12 (br. s., 2 H), 5.31 (s, 2 H),6.21 (d, J = 3.0 Hz, 1 H), 6.71-6.79 (m, 1 H), 6.86-6.94 (m, 3 H),6.97-7.05 (m, 2 H), 7.06-7.14 (m, 1 H), 7.20-7.27 (m, 1 H), 7.27-7.36(m, 2 H) A, 2.82 388  3

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.75 (t, J = 7.3 Hz, 3 H), 0.96-1.09 (m,2 H), 1.28-1.41 (m, 2 H), 3.25-3.33 (m, 2 H), 5.55 (s, 4 H), 5.85 (dd, J= 9.7, 2.6 Hz, 1 H), 5.98 (t, J = 5.0 Hz, 1 H), 6.08 (d, J = 3.0 Hz, 1H), 7.11 (td, J = 8.5, 3.1 Hz, 1 H), 7.30 (d, J = 3.0 Hz, 1 H), 7.70(dd, J = 8.8, 5.3 Hz, 1 H) A, 2.49 393  4

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.91 (t, J = 7.2 Hz, 3 H),1.30-1.44 (m, 2 H), 1.49-1.61 (m, 2 H), 3.34 (s, 3 H), 3.43 (td, J =7.1, 5.3 Hz, 2 H), 3.69-3.77 (m, 2 H), 4.20-4.29 (m, 2 H), 5.73 (br. s.,1 H), 6.20 (d, J = 3.0 Hz, 1 H), 6.86 (d, J = 3.2 Hz, 1 H), 7.11 (br.s., 1 H) A, 1.95 264  5

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.74 (t, J = 7.2 Hz, 3 H),0.90-1.07 (m, 2 H), 1.11-1.17 (m, 2 H), 3.18-3.28 (m, 2 H), 4.40 (br.s., 1 H), 4.94 (br. s., 2 H), 5.30 (s, 2 H), 6.23 (d, J = 3.0 Hz, 1 H),6.70 (d, J = 8.8 Hz, 1 H), 6.79 (d, J = 7.7 Hz, 1 H), 6.94-7.03 (m, 2H), 7.30 (td, J = 8.0, 5.8 Hz, 1 H) A, 2.29 314  6

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.72 (t, J = 7.2 Hz, 3 H),0.88-1.03 (m, 2 H), 1.14-1.27 (m, 2 H), 3.24 (td, J = 6.7, 5.3 Hz, 2 H),4.29 (br. s., 1 H), 4.89 (br. s., 2 H), 5.33 (s, 2 H), 6.24 (d, J = 3.0Hz, 1 H), 6.46-6.53 (m, 1 H), 6.99 (d, J = 3.0 Hz, 1 H), 7.10-7.22 (m, 2H), 7.55-7.60 (m, 1 H) A, 2.47 375  7

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.74 (t, J = 7.2 Hz, 3 H),0.86-1.01 (m, 2 H), 1.06-1.18 (m, 2 H), 3.12-3.22 (m, 2 H), 4.31 (t, J =5.0 Hz, 1 H), 5.18 (br. s., 2 H), 5.19-5.24 (m, 2 H), 6.20 (d, J = 3.0Hz, 1 H), 6.71 (d, J = 7.7 Hz, 1 H), 6.96 (d, J = 3.0 Hz, 1 H),7.21-7.47 (m, 8 H) A, 2.78 372  8

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.84 (t, J = 7.4 Hz, 3 H), 0.93 (t, J =7.3 Hz, 3 H), 1.06-1.27 (m, 2 H), 1.27-1.44 (m, 2 H), 1.50-1.66 (m, 4H), 3.44-3.54 (m, 2 H), 4.28 (t, J = 6.9 Hz, 2 H), 5.99 (d, J = 2.9 Hz,1 H), 6.17 (br. s., 2 H), 6.79 (br. s., 1 H), 7.28 (d, J = 2.9 Hz, 1 H)A, 2.28 262  9

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.86 (t, J = 7.4 Hz, 3 H), 0.91 (t,J = 7.3 Hz, 3 H), 1.36 (dq, J = 15.0, 7.4 Hz, 2 H), 1.52-1.65 (m, 2 H),1.76 (sxt, J = 7.3 Hz, 2 H), 3.52 (td, J = 7.1, 5.6 Hz, 2 H), 4.07 (t, J= 7.1 Hz, 2 H), 5.17-5.30 (m, 1 H), 5.52 (br. s., 2 H), 6.09 (d, J = 3.0Hz, 1 H), 6.88 (d, J = 3.0 Hz, 1 H) A, 2.06 248  10

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.92 (t, J = 7.3 Hz, 3 H), 1.38(dq, J = 15.0, 7.3 Hz, 2 H), 1.56-1.68 (m, 2 H), 3.49 (td, J = 7.1, 5.1Hz, 2 H), 5.28 (s, 2 H), 5.78 (br. s., 2 H), 6.18 (d, J = 3.0 Hz, 1 H),7.06 (d, J = 3.0 Hz, 1 H), 7.25-7.32 (m, 1 H), 7.34 (d, J = 7.7 Hz, 1H), 7.74 (td, J = 7.7, 1.7 Hz, 1 H), 8.48 (d, J = 4.4 Hz, 1 H), 8.58(br. s., 1 H) A, 2.14 297  11

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.94 (t, J = 7.4 Hz, 3 H), 1.39 (dq, J =14.9, 7.4 Hz, 2 H), 1.63 (quin, J = 7.3 Hz, 2 H), 2.90 (t, J = 7.1 Hz, 2H), 3.46-3.55 (m, 2 H), 4.55 (t, J = 7.1 Hz, 2 H), 5.94 (d, J = 3.0 Hz,1 H), 6.33 (br. s., 2 H), 6.97 (br. s., 1 H), 7.02-7.12 (m, 3 H),7.16-7.29 (m, 3 H) A, 2.42 310  12

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.90 (t, J = 7.3 Hz, 3 H), 1.34 (dq, J =14.9, 7.3 Hz, 2 H), 1.57 (quin, J = 7.3 Hz, 2 H), 1.91 (quin, J = 7.5Hz, 2 H), 2.41-2.48 (m, 2 H), 3.41-3.49 (m, 2 H), 4.29 (t, J = 7.0 Hz, 2H), 5.57 (s, 2 H), 5.94 (d, J = 2.9 Hz, 1 H), 6.32 (t, J = 5.4 Hz, 1 H),7.10-7.22 (m, 4 H), 7.22-7.31 (m, 2 H) A, 2.6  324  13

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.81 (t, J = 7.2 Hz, 3 H), 1.06(dq, J = 14.9, 7.3 Hz, 2 H), 1.22-1.35 (m, 2 H), 3.32 (td, J = 6.7, 5.4Hz, 2 H), 4.20 (br. s., 1 H), 4.51 (br. s., 2 H), 5.44 (s, 2 H), 6.31(d, J = 3.2 Hz, 1 H), 6.63 (d, J = 7.4 Hz, 1 H), 7.07 (d, J = 3.0 Hz, 1H), 7.16-7.25 (m, 1 H), 7.29-7.34 (m, 1 H), 7.47 (dd, J = 8.0, 1.2 Hz, 1H) A, 2.47 330  14

¹H NMR (400 MHz, CHLOROFORM-d) ppm 0.89 (t, J = 6.9 Hz, 3 H), 1.20-1.27(m, 1 H), 1.28-1.41 (m, 4 H), 1.64 (q, J = 7.0 Hz, 2 H), 3.61 (dd, J =11.2, 6.9 Hz, 1 H), 3.77 (dd, J = 11.0, 2.8 Hz, 1 H), 4.24 (td, J = 6.9,2.8 Hz, 1 H), 4.57 (br. s., 2 H), 5.48-5.68 (m, 2 H), 6.21 (d, J = 3.0Hz, 1 H), 6.74 (d, J = 6.8 Hz, 1 H), 7.10 (d, J = 3.0 Hz, 1 H), 7.35(dd, J = 8.5, 1.3 Hz, 1 H), 7.51 (dd, J = 8.4, 4.9 Hz, 1 H), 9.16 (dd, J= 5.0, 1.3 Hz, 1 H) B, 0.63 342  15

¹H NMR (400 MHz, METHANOL-d₄) δ ppm 0.88 (t, J = 7.3 Hz, 3 H), 1.13-1.32(m, 3 H), 1.46-1.69 (m, 3 H), 2.39 (t, J = 6.8 Hz, 1 H), 3.61 (d, J =5.5 Hz, 2 4 H), 4.31 (dd, J = 8.8, 5.0 Hz, 1 H), 5.62-5.87 (m, 2 H),6.13 (d, J = 3.0 Hz, 1 H), 7.39 (d, J = 3.0 Hz, 1 H), 7.46 (dd, J = 8.5,1.8 Hz, 1 H), 7.70 (dd, J = 8.5, 5.0 Hz, 1 H), 9.14 (dd, J = 4.9, 1.6Hz, 1 H) B, 0.55 328  16

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.77 (t, J = 7.2 Hz, 3 H), 1.02(dq, J = 14.9, 7.3 Hz, 2 H), 1.15-1.29 (m, 2 H), 3.25 (td, J = 6.8, 5.4Hz, 2 H), 4.08-4.22 (m, 1 H), 4.42 (br. s., 2 H), 5.23 (s, 2 H), 6.20(d, J = 3.0 Hz, 1 H), 6.83 (ddd, J = 8.5, 4.3, 2.2 Hz, 1 H), 6.95 (d, J= 3.0 Hz, 1 H), 7.04-7.12 (m, 2 H) A, 2.5  348  17

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.69 (t, J = 7.3 Hz, 3 H), 0.80-0.93 (m,2 H), 1.05-1.17 (m, 1 H), 1.34-1.45 (m, 1 H), 3.24 (br. s., 2 H),4.06-4.16 6 (m, 1 H), 4.63 (br. s., 1 H), 5.03 (d, J = 8.6 Hz, 1 H),5.24 (s, 2 H), 5.40-5.57 (m, 2 H), 5.99 (d, J = 3.1 Hz, 1 H), 6.98 (d, J= 7.0 Hz, 2 H), 7.22-7.35 (m, 3 H), 7.36 (d, J = 2.9 Hz, 1 H) B, 0.79326  18

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.89 (t, J = 7.4 Hz, 3 H), 1.18-1.39 (m,2 H), 1.45-1.63 (m, 2 H), 2.50 (s, 3 H), 3.36-3.46 (m, 2 H), 5.33 (s, 2H), 5.41 (s, 2 H), 5.96 (d, J = 2.9 Hz, 1 H), 7.03 (d, J = 7.6 Hz, 1 H),7.23 (d, J = 7.7 Hz, 1 H), 7.28 (t, J = 5.2 Hz, 1 H), 7.40 (d, J = 3.0Hz, 1 H), 7.71 (t, J = 7.7 Hz, 1 H) A, 1.68 311  19

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.99 (t, J = 7.4 Hz, 3 H), 1.26-1.43 (m,2 H), 1.45 (d, J = 6.3 Hz, 6 H), 1.67 (quin, J = 7.3 Hz, 2 H), 3.54-3.63(m, 2 H), 4.95 (dt, J = 12.9, 6.4 Hz, 1 H), 6.18 (d, J = 3.2 Hz, 1 H),6.73 (br. s., 2 H), 7.29 (br. s., 1 H), 7.57 (d, J = 3.2 Hz, 1 H) A,1.51 248  20

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.89 (t, J = 7.3 Hz, 3 H), 1.27 (dq, J =14.9, 7.4 Hz, 2 H), 1.51 (quin, J = 7.2 Hz, 2 H), 2.32 (s, 3 H),3.26-3.44 (m, 2 H), 5.33 (s, 2 H), 5.51 (s, 2 H), 5.83-5.87 (m, 1 H),5.97 (d, J = 3.0 Hz, 1 H), 6.11 (t, J = 5.3 Hz, 1 H), 7.29 (d, J = 3.0Hz, 1 H) A, 1.45 301  21

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.70 (t, J = 7.3 Hz, 3 H), 0.82-0.98 (m,2 H), 1.17-1.36 (m, 2 H), 1.37-1.48 (m, 1 H), 1.51-1.63 (m, 1 H), 3.21-63.31 (m, 2 H), 4.17-4.29 (m, 1 H), 4.49 (br. s., 1 H), 5.24 (d, J = 8.5Hz, 1 H), 5.30 (s, 2 H), 5.41-5.58 (m, 2 H), 6.00 (d, J = 3.0 Hz, 1 H),6.95 (s, 1 H), 6.96 (s, 1 H), 7.20-7.27 (m, 1 H), 7.27-7.34 (m, 2 H),7.36 (d, J = 3.0 Hz, 1 H) B, 0.83 340  22

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.87 (t, J = 7.3 Hz, 3 H), 1.15-1.32 (m,2 H), 1.45-1.59 (m, 1 H), 1.64 (td, J = 8.0, 5.0 Hz, 1 H), 3.50-3.54 (m,2 H), 3.72-3.79 (m, 1 H), 4.35 (td, J = 8.5, 4.8 Hz, 1 H), 5.45-5.64 (m,2 H), 6.14 (d, J = 3.0 Hz, 1 H), 6.77 (br. s., 2 H), 7.43 (ddd, J = 7.7,4.9, 1.0 Hz, 1 H), 7.51 (d, J = 7.8 Hz, 1 H), 7.63 (d, J = 3.0 Hz, 1 H),7.91 (td, J = 7.7, 1.8 Hz, 1 H), 8.42 (d, J = 7.8 Hz, 1 H), 8.50-8.58(m, 1 H) B, 0.69 327  23

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.67 (t, J = 7.4 Hz, 3 H), 1.25(sxt, J = 7.3 Hz, 2 H), 3.24 (td, J = 7.0, 5.4 Hz, 2 H), 4.65 (br. s., 1H), 5.16 (br. s., 2 H), 5.39 (s, 2 H), 6.30 (d, J = 3.0 Hz, 1 H),7.03-7.13 (m, 3 H), 7.32-7.47 (m, 3 H) A, 2.15 282  24

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.82 (t, J = 7.40 Hz, 3 H) 1.13-1.24 (m,2 H) 1.43-1.54 (m, 2 H) 1.55-1.76 (m, 2 H) 3.38-3.46 (m, 2 H) 4.28-4.37(m, 1 H) 4.47 (br. s., 1 H) 5.35 (s, 2 H) 5.43-5.51 (m, 2 H) 5.97 (d, J= 3.01 Hz, 1 H) 6.88 (d, J = 8.28 Hz, 1 H) 7.26 (d, J = 7.78 Hz, 1 H)7.37 (ddd, J = 7.53, 5.02, 1.00 Hz, 1 H) 7.43 (d, J = 3.01 Hz, 1 H) 7.84(td, J = 7.65, 1.76 Hz, 1 H) 8.53 (dt, J = 4.00, 0.80 Hz, 1 H) B, 0.71341  25

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.74-0.85 (m, 3 H) 1.09-1.18 (m, 2 H)1.18-1.30 (m, 2 H) 1.40-1.56 (m, 2 H) 1.56-1.65 (m, 1 H) 1.65-1.76 (m, 1H) 3.34-3.45 (m, 2 H) 4.24-4.34 (m, 1 H) 4.47 (br. s., 1 H) 5.22 (s, 2H) 5.39-5.53 (m, 2 H) 5.96 (d, J = 2.76 Hz, 1 H) 6.75 (d, J = 8.28 Hz, 1H) 7.23 (d, J = 7.78 Hz, 1 H) 7.37 (ddd, J = 7.53, 4.89, 1.13 Hz, 1 H)7.41 (d, J = 3.01 Hz, 1 H) 7.83 (td, J = 7.72, 1.88 Hz, 1 H) 8.50-8.55(m, 1 H) B, 0.8  355  26

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.73 (t, J = 7.4 Hz, 3 H), 0.77-0.93 (m,2 H), 1.01-1.19 (m, 3 H), 1.38-1.51 (m, 1 H), 3.23-3.30 (m, 2 H), 4.04-64.17 (m, 1 H), 4.66 (br. s., 1 H), 5.12 (d, J = 8.5 Hz, 1 H), 5.35 (s, 2H), 5.40-5.60 (m, 2 H), 6.01 (d, J = 3.0 Hz, 1 H), 6.95-7.03 (m, 2 H),7.22-7.35 (m, 3 H), 7.38 (d, J = 3.0 Hz, 1 H) B, 0.86 340  27

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.74 (d, J = 6.52 Hz, 3 H) 0.82 (d, J =6.78 Hz, 3 H) 0.92 (t, J = 7.28 Hz, 3 H) 1.30-1.46 (m, 2 H) 1.50-1.69(m, 2 H) 1.87-2.01 (m, 1 H) 3.43-3.58 (m, 2 H) 3.88 (dd, J = 14.68, 8.16Hz, 1 H) 4.12 (dd, J = 14.56, 6.53 Hz, 1 H) 4.28 (m, J = 8.40, 3.90 Hz,1 H) 4.79 (br. s., 1 H) 5.22 (s, 2 H) 5.41 (d, J = 8.53 Hz, 1 H) 5.89(d, J = 3.01 Hz, 1 H) 7.15 (d, J = 3.01 Hz, 1 H) B, 0.76 292  28

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.69 (d, J = 6.9 Hz, 3 H), 0.79 (d, J =6.9 Hz, 3 H), 0.82-0.91 (m, 3 H), 1.20-1.39 (m, 4 H), 1.49-1.65 (m, 2H), 1.66-6 1.79 (m, 2 H), 1.83-1.97 (m, 1 H), 3.43-3.58 (m, 2 H), 3.86(dd, J = 14.5, 8.5 Hz, 1 H), 4.12 (dd, J = 14.5, 6.5 Hz, 1 H), 4.27-4.44(m, 1 H), 4.71 (br. s., 1 H), 5.21 (s, 2 H), 5.75 (d, J = 8.5 Hz, 1 H),5.87 (d, J = 2.8 Hz, 1 H), 7.12 (d, J = 3.2 Hz, 1 H) B, 0.89 320  29

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.75-0.85 (m, 3 H), 1.02 (d, J = 7.0 Hz,2 H), 1.11-1.26 (m, 2 H), 1.34 (d, J = 7.6 Hz, 2 H), 3.28 (s, 2 H), 5.22(s, 2 H), 5.49 (s, 2 H), 5.76 (s, 1 H), 5.98 (d, J = 3.0 Hz, 1 H), 6.97(d, J = 6.7 Hz, 2 H), 7.17-7.35 (m, 4 H) A, 2.47 310  30

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.76 (dd, J = 11.42, 6.65 Hz, 6 H) 0.90(t, J = 7.28 Hz, 3 H) 1.26-1.37 (m, 2 H) 1.53-1.63 (m, 1 H) 1.63-1.73(m, 1 H) 1.74-1.90 (m, 3 H) 3.49-3.62 (m, 2 H) 4.11-4.22 (m, 2 H) 4.55(m, J = 6.50 Hz, 1 H) 4.79 (t, J = 4.52 Hz, 1 H) 6.16 (d, J = 3.01 Hz, 1H) 7.24 (d, J = 8.28 Hz, 1 H) 7.33 (br. s., 2 H) 7.44 (d, J = 2.76 Hz, 1H) 12.35 (br. s., 1 H) B, 0.82 306  31

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.64-0.75 (m, 3 H), 0.77-0.97 (m, 2 H),1.02-1.21 (m, 1 H), 1.30-1.50 (m, 1 H), 3.33 (d, J = 4.3 Hz, 2 H), 4.15(dd, J = 9.2, 4.5 Hz, 1 H), 4.69 (br. s., 1 H), 5.34 (d, J = 8.5 Hz, 1H), 5.42-5.64 (m, 2 H), 5.71 (br. s., 2 H), 6.06 (d, J = 3.0 Hz, 1 H),6.99 (d, J = 6.6 Hz, 2 H), 7.17-7.37 (m, 3 H), 7.44 (d, J = 3.0 Hz, 1 H)A, 2.07 326  32

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.57 (d, J = 6.6 Hz, 6 H), 1.19 (s,2 H), 1.33-1.52 (m, 1 H), 3.05 (dd, J = 6.8, 5.6 Hz, 2 H), 4.61-4.78 (m,1 H), 5.32 (s, 2 H), 6.25 (d, J = 3.0 Hz, 1 H), 6.97-7.06 (m, 3 H),7.26-7.39 (m, 3 H) A, 2.25 296  33

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.74-0.82 (m, 3 H), 0.86 (d, J =6.5 Hz, 3 H), 0.93-1.28 (m, 4 H), 4.01-4.22 (m, 1 H), 4.39 (d, J = 7.8Hz, 1 H), 5.05 (br. s., 2 H), 5.37 (s, 2 H), 6.29 (d, J = 3.0 Hz, 1 H),7.02-7.13 (m, 3 H), 7.32-7.47 (m, 3 H) A, 2.4 310  34

¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.24 (s, 3 H), 3.35-3.44 (m, 2 H), 3.57(q, J = 5.6 Hz, 2 H), 5.55 (s, 2 H), 5.97 (br. s., 2 H), 6.09 (d, J =2.9 Hz, 1 H), 6.30 (br. s., 1 H), 7.05-7.14 (m, 2 H), 7.25-7.41 (m, 3H), 7.46 (d, J = 3.0 Hz, 1 H) A, 1.81 298  35

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.98 (t, J = 7.1 Hz, 3 H), 3.23-3.44 (m,2 H), 5.43 (s, 2 H), 5.49 (s, 2 H), 5.96-6.07 (m, 2 H), 7.02 (d, J = 6.7Hz, 2 H), 7.17-7.38 (m, 4 H) A, 1.96 268  36

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.56 (quin, J = 6.4 Hz, 2 H), 3.24-3.44(m, 4 H), 4.45-4.58 (m, 1 H), 5.49 (s, 2 H), 5.61 (br. s., 2 H), 6.03(d, J = 2.9 Hz, 1 H), 6.19 (t, J = 5.0 Hz, 1 H), 6.96-7.04 (m, 2 H),7.19-7.34 (m, 3 H), 7.37 (d, J = 3.0 Hz, 1 H) A, 1.61 298  37

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.74 (t, J = 7.3 Hz, 3 H), 0.80-0.95 (m,2 H), 1.02-1.17 (m, 2 H), 1.19-1.48 (m, 3 H), 1.51-1.64 (m, 1 H), 3.21-63.27 (m, 2 H), 4.20 (tt, J = 8.5, 4.0 Hz, 1 H), 4.49 (br. s., 1 H),5.18-5.32 (m, 3 H), 5.40-5.59 (m, 2 H), 6.00 (d, J = 3.1 Hz, 1 H), 6.96(d, J = 7.3 Hz, 2 H), 7.19-7.39 (m, 4 H) B, 0.92 354  38

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.62 (d, J = 4.0 Hz, 3 H), 0.65 (d, J =6.8 Hz, 3 H), 0.95-1.04 (m, 1 H), 1.35-1.47 (m, 1 H), 1.89 (s, 3 H),3.35-3.46 6 (m, 2 H), 3.98-4.07 (m, 1 H), 5.06 (d, J = 8.8 Hz, 1 H),5.42-5.60 (m, 4 H), 6.01 (d, J = 2.9 Hz, 1 H), 6.94-6.98 (m, 2 H),7.23-7.28 (m, 1 H), 7.29-7.35 (m, 2 H), 7.38 (d, J = 3.1 Hz, 1 H) B,0.84 340  39

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.63-0.73 (m, 3 H), 0.75-0.95 (m, 2 H),1.18-1.36 (m, 2 H), 1.48 (dd, J = 8.9, 4.7 Hz, 1 H), 1.53-1.64 (m, 1 H),3.20 6-3.28 (m, 2 H), 4.13-4.29 (m, 1 H), 4.50 (t, J = 5.4 Hz, 1 H),5.28 (s, 2 H), 5.37 (d, J = 8.6 Hz, 1 H), 5.47-5.69 (m, 2 H), 6.04 (d, J= 3.1 Hz, 1 H), 6.81 (d, J = 5.9 Hz, 2 H), 7.36 (d, J = 2.9 Hz, 1 H),8.40-8.50 (m, 2 H) B, 0.57 341  40

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.76-0.82 (m, 3 H), 0.87-1.00 (m, 2H), 1.02-1.22 (m, 5 H), 1.28-1.41 (m, 1 H), 1.72-1.85 (m, 1 H), 3.34(td, J = 11.6, 2.4 Hz, 1 H), 3.44-3.55 (m, 1 H), 4.12-4.27 (m, 2 H),4.58 (br. s., 2 H), 5.26-5.45 (m, 2 H), 6.27 (d, J = 3.1 Hz, 1 H),6.89-6.97 (m, 2 H), 7.06 (d, J = 3.1 Hz, 1 H), 8.55-8.62 (m, 2 H) B,0.64 355  41

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.65-0.80 (m, 3 H) 0.89-1.07 (m, 2H) 1.11-1.22 (m, 2 H) 3.14-3.28 (m, 2 H) 3.73 (s, 3 H) 4.76 (br. s., 1H) 5.08-5.24 (m, 2 H) 5.27 (s, 2 H) 6.18 (d, J = 3.02 Hz, 1 H) 6.84 (d,J = 8.66 Hz, 2 H) 6.94 (d, J = 8.66 Hz, 2 H) 7.00 (d, J = 3.02 Hz, 1 H)A, 2.26 326  42

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.70-0.87 (m, 3 H) 0.97-1.14 (m, 2 H)1.31-1.46 (m, 2 H) 3.36-3.40 (m, 2 H) 5.52 (s, 2 H) 5.62 (s, 2 H) 6.05(d, J = 3.02 Hz, 1 H) 6.11 (s, 1 H) 6.90-7.09 (m, 2 H) 7.09-7.24 (m, 2H) 7.39 (d, J = 3.02 Hz, 1 H) A, 2.23 314  43

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.67-0.85 (m, 3 H) 0.94-1.13 (m, 2H) 1.16-1.33 (m, 2 H) 3.16-3.43 (m, 2 H) 4.33 (br. s., 1 H) 4.54 (br.s., 2 H) 5.32 (s, 2 H) 6.21 (d, J = 3.02 Hz, 1 H) 6.67 (t, J = 7.35 Hz,1 H) 6.99 (d, J = 3.02 Hz, 1 H) 7.00-7.13 (m, 2 H) 7.22-7.32 (m, 1 H) A,2.27 314  44

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm −0.07-0.07 (m, 2 H) 0.21-0.43 (m, 3H) 0.66-0.75 (m, 3 H) 0.76-0.95 (m, 1 H) 3.22-3.51 (m, 2 H) 4.86 (br.s., 1 H) 5.15 (br. s., 2 H) 5.41 (s, 2 H) 6.33 (d, J = 3.02 Hz, 1 H)7.07 (br. s., 1 H) 7.10 (s, 2 H) 7.35-7.47 (m, 3 H) A, 2.46 322  45

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 4.21 (d, J = 4.95 Hz, 2 H) 4.48(br. s., 1 H) 4.70 (br. s., 2 H) 5.18-5.30 (m, 2 H) 5.97 (s, 1 H) 6.22(d, J = 3.02 Hz, 1 H) 6.90 (dd, J = 6.53, 2.13 Hz, 2 H) 6.98 (s, 1 H)7.02 (d, J = 3.02 Hz, 1 H) 7.20-7.29 (m, 4 H) A, 2.09 320  46

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm −0.12-0.09 (m, 2 H) 0.24-0.46 (m, 2H) 0.89 (d, J = 5.64 Hz, 3 H) 2.84-3.06 (m, 1 H) 3.08-3.25 (m, 1 H) 4.51(br. s., 1 H) 4.63 (br. s., 2 H) 5.34 (s, 2 H) 6.23 (d, J = 3.02 Hz, 1H) 7.03 (d, J = 2.75 Hz, 2 H) 7.06 (br. s., 1 H) 7.27-7.40 (m, 3 H) A,2.26 308  47

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.42 (s, 3 H) 1.58 (s, 3 H)3.66-3.80 (m, 2 H) 4.42 (br. s., 1 H) 4.71-4.88 (m, 1 H) 5.02 (br. s., 2H) 5.28 (s, 2 H) 6.21 (d, J = 3.02 Hz, 1 H) 6.96-7.01 (m, 2 H) 7.02 (s,1 H) 7.24-7.41 (m, 3 H) A, 2.32 308  48

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.28 (s, 3 H) 4.46 (d, J = 5.22 Hz,2 H) 4.65 (br. s., 2 H) 4.92 (br. s., 1 H) 5.30 (s, 2 H) 5.54 (s, 1 H)6.22 (d, J = 3.02 Hz, 1 H) 6.89-7.01 (m, 2 H) 7.03 (d, J = 3.16 Hz, 1 H)7.21-7.27 (m, 3 H) A, 1.97 335  49

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.79 (s, 3 H) 4.44 (d, J = 4.67 Hz,2 H) 5.33 (s, 2 H) 5.60 (br. s., 1 H) 5.84 (d, J = 2.06 Hz, 1 H) 6.28(d, J = 3.02 Hz, 1 H) 6.43 (br. s., 2 H) 6.96 (dd, J = 6.53, 2.82 Hz, 2H) 7.02 (d, J = 3.02 Hz, 1 H) 7.18 (d, J = 2.20 Hz, 1 H) 7.21-7.28 (m, 3H) A, 1.83 334  50

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.83-0.91 (m, 3 H) 1.30-1.41 (m, 2H) 1.57-1.67 (m, 2 H) 3.44-3.60 (m, 2 H) 5.41 (s, 2 H) 6.22 (br. s, 2 H)6.21 (d, J = 3.02 Hz, 1 H) 7.05 (d, J = 3.02 Hz, 1 H) 7.55-7.65 (m, 2 H)7.70 (t, J = 7.49 Hz, 1 H) 7.76-7.86 (m, 1 H) 7.95 (d, J = 8.11 Hz, 1 H)8.23 (br. s., 1 H) 9.12 (s, 1 H) A, 2.52 347  51

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.71 (d, J = 6.32 Hz, 6 H)0.74-0.86 (m, 1 H) 0.93-1.05 (m, 2 H) 3.15-3.28 (m, 2 H) 4.59 (br. s., 1H) 5.29 (s, 2 H) 6.18 (br. s., 2 H) 6.27 (d, J = 3.02 Hz, 1 H) 6.97-7.01(m, 2 H) 7.02 (br. s., 1 H) 7.26-7.42 (m, 3 H) A, 2.45 310  52

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.89-0.95 (m, 1 H) 0.92 (t, J =7.35 Hz, 3 H) 1.00-1.26 (m, 4 H) 1.31-1.44 (m, 2 H) 1.47-1.75 (m, 8 H)3.43-3.59 (m, 2 H) 3.83 (d, J = 7.29 Hz, 2 H) 4.73 (br. s., 1 H) 4.93(br. s., 2 H) 6.08 (d, J = 3.02 Hz, 1 H) 6.81 (d, J = 3.02 Hz, 1 H) A,2.68 302  53

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.19-0.35 (m, 2 H) 0.50-0.65 (m, 2H) 0.69-0.86 (m, 1 H) 0.91 (t, J = 7.29 Hz, 3 H) 1.33-1.45 (m, 2 H)1.49-1.65 (m, 2 H) 3.50 (td, J = 7.11, 5.57 Hz, 2 H) 4.00 (d, J = 6.05Hz, 2 H) 4.68 (br. s., 2 H) 4.80 (br. s., 1 H) 6.10 (d, J = 3.02 Hz, 1H) 6.93 (d, J = 3.02 Hz, 1 H) A, 2.19 260  54

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.69-0.74 (m, 3 H) 0.89-0.97 (m, 2H) 1.07-1.13 (m, 2 H) 2.21 (s, 3 H) 3.14-3.27 (m, 2 H) 4.66 (br. s., 1H) 5.24 (s, 2 H) 6.40 (br. s., 2 H) 6.78-6.86 (m, 1 H) 6.92-7.05 (m, 2H) 7.26-7.41 (m, 3 H) A, 2.46 310  55

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.96 (t, J = 7.29 Hz, 3 H)1.38-1.57 (m, 2 H) 1.58-1.75 (m, 2 H) 3.54-3.64 (m, 2 H) 4.29-4.42 (m, 2H) 4.56 (t, J = 4.88 Hz, 2 H) 4.59 (br. s., 2 H) 5.96 (br. s., 1 H) 6.26(d, J = 3.02 Hz, 1 H) 6.79-6.91 (m, 2 H) 6.99 (d, J = 3.02 Hz, 1 H)7.00-7.08 (m, 1 H) 7.28-7.34 (m, 2 H) A, 2.47 326  56

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.93 (t, J = 7.35 Hz, 3 H)1.36-1.52 (m, 2 H) 1.52-1.71 (m, 2 H) 3.46-3.65 (m, 2 H) 5.35 (s, 2 H)6.06 (br. s., 2 H) 6.22 (d, J = 3.02 Hz, 1 H) 7.13 (d, J = 3.02 Hz, 1 H)7.31 (t, J = 5.02 Hz, 1 H) 8.02 (br. s., 1 H) 8.71 (d, J = 5.09 Hz, 2 H)C, 4.68 298  57

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.79 (t, J = 7.29 Hz, 3 H) 1.22(dd, J = 15.19, 7.49 Hz, 2 H) 1.39-1.56 (m, 2 H) 3.29-3.45 (m, 2 H) 4.63(br. s., 2 H) 5.44 (s, 2 H) 6.17 (d, J = 3.02 Hz, 1 H) 7.00 (br. s., 1H) 7.09 (d, J = 3.02 Hz, 1 H) 7.18-7.28 (m, 1 H) 7.42-7.57 (m, 1 H)7.62-7.83 (m, 2 H) 7.97 (d, J = 8.39 Hz, 1 H) 8.10 (d, J = 8.39 Hz, 1 H)A, 2.49 347  58

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.69-0.74 (m, 3 H) 0.89-0.97 (m, 2H) 1.07-1.13 (m, 2 H) 2.21 (s, 3 H) 3.14-3.27 (m, 2 H) 4.66 (br. s., 1H) 5.24 (s, 2 H) 6.40 (br. s., 2 H) 6.78-6.86 (m, 1 H) 6.92-7.05 (m, 2H) 7.26-7.41 (m, 3 H) A, 2.56 310  59

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.89 (t, J = 7.22 Hz, 3 H)1.26-1.40 (m, 2 H) 1.41-1.57 (m, 2 H) 1.70-1.77 (m, 6 H) 3.32-3.51 (m, 2H) 4.47 (br. s., 2 H) 4.66 (d, J = 5.64 Hz, 2 H) 4.98 (br. s., 1 H)5.28-5.41 (m, 1 H) 6.06 (d, J = 3.02 Hz, 1 H) 6.84 (d, J = 3.02 Hz, 1 H)A, 2.37 274  60

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 4.47 (br. s., 2 H) 4.74 (d, J =5.50 Hz, 2 H) 5.15 (t, J = 5.16 Hz, 1 H) 5.32 (s, 2 H) 6.22 (d, J = 3.02Hz, 1 H) 6.94-7.01 (m, 2 H) 7.03 (d, J = 3.02 Hz, 1 H) 7.14 (d, J = 3.30Hz, 1 H) 7.17-7.27 (m, 3 H) 7.58 (d, J = 3.30 Hz, 1 H) A, 1.86 337  61

¹H NMR (300 MHz, chloroform-d) δ ppm 4.38 (d, J = 5.36 Hz, 2 H) 4.49(br. s., 2 H) 4.54-4.66 (m, 1 H) 5.26 (s, 2 H) 6.21 (d, J = 3.02 Hz, 1H) 6.84-6.92 (m, 2 H) 7.00-7.08 (m, 2 H) 7.08-7.14 (m, 1 H) 7.14-7.23(m, 3 H) 8.15-8.23 (m, 1 H) 8.36-8.44 (m, 1 H) A, 1.28 331  62

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.92 (t, J = 7.35 Hz, 3 H) 1.37(dq, J = 14.90, 7.31 Hz, 2 H) 1.52-1.63 (m, 2 H) 1.65-1.78 (m, 2 H)1.78-1.90 (m, 2 H) 1.91-2.05 (m, 2 H) 2.47-2.83 (m, 2 H) 3.41-3.54 (m, 1H) 4.05 (d, J = 7.01 Hz, 2 H) 4.73 (br. s., 1 H) 4.89 (br. s., 2 H) 6.09(d, J = 3.02 Hz, 1 H) 6.85 (d, J = 3.02 Hz, 1 H) A, 2.33 274  63

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.75 (t, J = 7.3 Hz, 3 H), 0.98-1.06 (m,2 H), 1.32 (quin, J = 7.2 Hz, 2 H), 2.27 (s, 3 H), 3.24-3.28 (m, 2 H),5.25 (br. s., 6 2 H), 5.44 (s, 2 H), 5.75 (t, J = 5.4 Hz, 1 H), 5.87 (s,1 H), 6.87 (d, J = 7.0 Hz, 2 H), 7.19-7.25 (m, 1 H), 7.25-7.32 (m, 2 H)B, 0.97 310  64

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.75 (t, J = 7.30 Hz, 3 H)0.89-1.06 (m, 2 H) 1.11-1.29 (m, 2 H) 3.24-3.34 (m, 2 H) 5.16 (br. s., 1H) 5.47 (s, 2 H) 5.96 (br. s., 2 H) 6.21 (d, J = 3.02 Hz, 1 H) 7.00 (d,J = 3.02 Hz, 1 H) 7.18-7.26 (m, 2 H) 8.33-8.42 (m, 1 H) 8.49-8.59 (m, 1H) C, 4.21 297  65

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.95 (t, J = 7.29 Hz, 3 H)1.30-1.54 (m, 2 H) 1.70 (quin, J = 7.32 Hz, 2 H) 3.50 (td, J = 7.11,5.02 Hz, 2 H) 4.76 (br. s., 2 H) 5.77 (s, 2 H) 6.14 (d, J = 3.02 Hz, 1H) 7.17-7.21 (m, 1 H) 7.62-7.73 (m, 3 H) 7.80-7.87 (m, 1 H) 8.25-8.34(m, 1 H) 8.37 (d, J = 5.77 Hz, 1 H) 8.59 (br. s., 1 H) A, 2.61 347  66

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.90 (t, J = 7.22 Hz, 3 H)1.25-1.40 (m, 2 H) 1.43-1.54 (m, 2 H) 3.29 (td, J = 7.11, 5.57 Hz, 2 H)3.87 (br. s., 1 H) 4.07-4.22 (m, 2 H) 4.23-4.31 (m, 2 H) 4.61 (br. s., 2H) 6.06 (t, J = 2.06 Hz, 2 H) 6.14 (d, J = 3.02 Hz, 1 H) 6.29 (t, J =2.06 Hz, 2 H) 6.70 (d, J = 3.02 Hz, 1 H) A, 2.15 299  67

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.92 (t, J = 7.29 Hz, 3 H)1.26-1.47 (m, 2 H) 1.49-1.67 (m, 2 H) 2.34-2.46 (m, 4 H) 2.72-2.81 (m, 2H) 3.52 (td, J = 7.22, 5.77 Hz, 2 H) 3.57-3.64 (m, 4 H) 4.17-4.24 (m, 2H) 5.75-6.08 (m, 2 H) 6.19 (d, J = 3.02 Hz, 1 H) 6.87 (d, J = 3.02 Hz, 1H) 8.19 (br. s., 1 H) A, 1.16 319  68

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.90 (t, J = 7.29 Hz, 3 H)1.30-1.46 (m, 2 H) 1.58-1.73 (m, 2 H) 3.53 (td, J = 7.01, 5.22 Hz, 2 H)5.32 (s, 2 H) 5.78-6.11 (m, 2 H) 6.18 (d, J = 3.02 Hz, 1 H) 6.78-6.84(m, 1 H) 7.01 (d, J = 3.02 Hz, 1 H) 7.18-7.24 (m, 2 H) 7.46 (d, J = 9.07Hz, 1 H) 7.54 (s, 1 H) 8.06 (d, J = 6.74 Hz, 1 H) 8.92-9.11 (m, 0 H) A,1.76 336  69

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.74 (t, J = 7.30 Hz, 3 H)0.90-1.12 (m, 2 H) 1.14-1.27 (m, 2 H) 3.20-3.28 (m, 2 H) 3.85 (s, 3 H)4.55 (br. s., 3 H) 5.22-5.27 (m, 2 H) 6.18 (d, J = 3.02 Hz, 1 H) 6.62(d, J = 7.01 Hz, 1 H) 6.82 (t, J = 7.56 Hz, 1 H) 6.87 (d, J = 8.25 Hz, 1H) 6.98 (d, J = 3.02 Hz, 1 H) 7.20-7.27 (m, 1 H) A, 2.44 326  70

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.74 (t, J = 7.40 Hz, 3 H)0.88-1.09 (m, 2 H) 1.10-1.25 (m, 2 H) 3.18-3.28 (m, 2 H) 4.21 (br. s., 1H) 4.66 (br. s., 2 H) 5.23 (s, 2 H) 6.22 (d, J = 3.16 Hz, 2 H) 6.89 (d,J = 5.77 Hz, 1 H) 6.96 (d, J = 3.02 Hz, 1 H) 8.51-8.59 (m, 2 H) A, 1.14297  71

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.91 (t, J = 7.29 Hz, 3 H)1.27-1.45 (m, 2 H) 1.49-1.67 (m, 3 H) 1.85 (d, J = 7.01 Hz, 1 H)1.91-2.12 (m, 2 H) 3.39-3.49 (m, 2 H) 3.72 (t, J = 6.67 Hz, 2 H) 4.02(dd, J = 15.81, 4.54 Hz, 1 H) 4.12-4.23 (m, 1 H) 4.42 (dd, J = 15.74,1.72 Hz, 1 H) 5.76-6.13 (m, 2 H) 6.23 (d, J = 3.02 Hz, 1 H) 6.82 (d, J =3.02 Hz, 1 H) 7.61-7.79 (m, 1 H) A, 2.17 290  72

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.78 (t, J = 7.30 Hz, 3 H)1.00-1.15 (m, 2 H) 1.16-1.29 (m, 2 H) 3.19-3.31 (m, 2 H) 4.46 (br. s., 1H) 4.59 (br. s., 2 H) 5.27 (s, 2 H) 6.17 (d, J = 3.02 Hz, 1 H) 6.82 (dd,J = 4.95, 1.10 Hz, 1 H) 6.91-6.95 (m, 1 H) 6.97 (d, J = 3.02 Hz, 1 H)7.34 (dd, J = 4.95, 2.89 Hz, 1 H) A, 2.27 302  73

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.79 (t, J = 7.20 Hz, 3 H)1.02-1.33 (m, 4 H) 1.90-2.08 (m, 2 H) 3.27 (td, J = 6.80, 5.36 Hz, 2 H)4.58 (br. s., 2 H) 5.41 (s, 2 H) 6.19 (d, J = 3.02 Hz, 1 H) 6.67-6.84(m, 1 H) 6.93 (dd, J = 5.02, 3.51 Hz, 1 H) 6.98 (d, J = 3.16 Hz, 1 H)7.26 (dd, J = 5.09, 0.96 Hz, 1 H) A, 2.28 302  74

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.73 (t, J = 7.20 Hz, 3 H) 0.89 (d,J = 6.46 Hz, 3 H) 0.93-1.07 (m, 2 H) 1.07-1.29 (m, 2 H) 4.05-4.20 (m, 1H) 4.43 (d, J = 7.84 Hz, 1 H) 5.16-5.29 (m, 2 H) 5.33 (s, 2 H) 6.25 (d,J = 3.02 Hz, 1 H) 6.68 (t, J = 7.49 Hz, 1 H) 7.02-7.13 (m, 3 H)7.23-7.34 (m, 1 H) A, 2.53 328  75

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.72 (t, J = 7.00 Hz, 3 H) 0.83 (d,J = 6.46 Hz, 3 H) 0.86-1.07 (m, 2 H) 1.08-1.22 (m, 2 H) 3.74 (s, 3 H)4.07 (s, 1 H) 4.57-4.62 (m, 1 H) 5.23 (s, 2 H) 5.30-5.55 (m, 2 H) 6.24(d, J = 3.02 Hz, 1 H) 6.82-6.89 (m, 2 H) 6.90-6.97 (m, 2 H) 7.02 (d, J =3.02 Hz, 1 H) A, 2.58 340  76

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.68 (t, J = 7.20 Hz, 1 H) 0.81-0.95 (m,2 H) 0.96-1.14 (m, 2 H) 1.16-1.36 (m, 2 H) 1.36-1.62 (m, 2 H) 3.21-3.28(m, 2 H) 4.09-4.25 (m, 1 H) 4.39-4.48 (m, 1 H) 5.15-5.26 (m, 2 H)5.32-5.39 (m, 1 H) 5.40-5.50 (m, 1 H) 5.55-5.65 (m, 1 H) 5.96 (d, J =2.90 Hz, 1 H) 6.34-6.44 (m, 1 H) 6.97-7.05 (m, 1 H) 7.10-7.30 (m, 3 H)A, 2.34 372  77

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.73 (t, J = 7.20 Hz, 3 H)0.80-1.00 (m, 4 H) 1.00-1.33 (m, 2 H) 1.47-1.83 (m, 3 H) 3.15-3.26 (m, 1H) 3.32-3.43 (m, 1 H) 3.72 (s, 3 H) 4.01-4.14 (m, 1 H) 4.22 (d, J = 8.25Hz, 1 H) 4.40 (br. s., 2 H) 5.16-5.29 (m, 2 H) 6.18 (d, J = 3.02 Hz, 1H) 6.80-6.95 (m, 4 H) 7.03 (d, J = 3.02 Hz, 1 H) A, 2.34 384  78

¹H NMR (300 MHz, CDCl₃) δ 7.31 (t, J = 7.9 Hz, 1 H), 7.12 (d, J = 3.0Hz, 1 H), 6.95 (d, J = 8.5 Hz, 1 H), 6.89 (d, J = 7.6 Hz, 1 H), 6.63 (d,J = 6.9 Hz, 1 H), 6.29 (d, J = 3.0 Hz, 1 H), 5.33 (d, J = 6.0 Hz, 2 H),5.02 (s, 2 H), 4.60 (s, 1 H), 4.20 (s, 1 H), 3.92 (s, 3 H), 3.50-3.35(m, 1 H), 3.24 (td, J = 11.6, 2.7 Hz, 1 H), 1.86-1.69 (m, 2 H),1.44-1.29 (m, 1 H), 1.29-0.92 (m, 6 H), 0.81 (t, J = 7.2 Hz, 3 H). A,2.42 384  79

¹H NMR (300 MHz, CDCl₃) δ 7.34 (t, J = 7.8 Hz, 1 H), 7.10 (d, J = 3.0Hz, 1 H), 6.97 (d, J = 8.5 Hz, 1 H), 6.91 (d, J = 7.4 Hz, 1 H), 6.65 (d,J = 7.4 Hz, 1 H), 6.31 (d, J = 3.0 Hz, 1 H), 5.33 (s, 2 H), 4.76 (d, J =7.2 Hz, 1 H), 4.18 (dt, J = 14.2, 6.9 Hz, 1 H), 3.93 (s, 3 H), 1.24-0.95(m, 6 H), 0.91 (d, J = 6.5 Hz, 3 H), 0.79 (t, J = 7.0 Hz, 3 H). A, 2.60340  80

¹H NMR (300 MHz, CDCl₃) δ 7.24 (t, J = 7.8 Hz, 1 H), 7.05 (d, J = 3.0Hz, 1 H), 6.88 (d, J = 8.3 Hz, 1 H), 6.83 (t, J = 7.8 Hz, 1 H), 6.56 (d,J = 7.3 Hz, 1 H), 6.21 (d, J = 3.0 Hz, 1 H), 5.26 (2d, J = 6.0 Hz, 2 H),4.90 (s, 2 H), 4.52 (d, J = 8.3 Hz, 1 H), 4.17 (dd, J = 9.1, 6.4 Hz, 1H), 3.86 (s, 3 H), 3.36 (ddd, J = 11.8, 5.0, 2.7 Hz, 1 H), 3.17 (td, J =11.5, 2.7 Hz, 1 H), 1.77-1.60 (m, 1 H), 1.37-1.13 (m, 2 H), 1.09-0.75(m, 4 H), 0.71 (t, J = 7.0 Hz, 3 H). A, 2.25 370  81

¹H NMR (300 MHz, CDCl₃) δ 7.27 (dd, J = 13.6, 6.2 Hz, 1 H), 7.09 (d, J =10.1 Hz, 1 H), 7.05 (d, J = 3.1 Hz, 1 H), 7.02 (d, J = 7.7 Hz, 1 H),6.63 (t, J = 7.2 Hz, 1 H), 6.24 (d, J = 3.0 Hz, 1 H), 5.42-5.25 (m, 2H), 4.78 (s, 2 H), 4.43 (s, 1 H), 4.20 (s, 1 H), 3.48-3.36 (m, 1 H),3.25 (td, J = 11.6, 2.5 Hz, 1 H), 1.82-1.65 (m, 2 H), 1.39-0.86 (m, 5H), 0.71 (t, J = 7.1 Hz, 3 H). A, 2.19 358  82

¹H NMR (300 MHz, CDCl₃) δ 6.92 (d, J = 3.0 Hz, 1 H), 6.16 (J = 3.0 Hz, 1H), 5.85 (s, 1 H), 5.51 (s, 2 H), 4.60-4.39 (m, 1 H), 4.24-4.04 (m, 2H), 3.81 (d, J = 6.6 Hz, 2 H), 2.71 (dt, J = 14.9, 7.5 Hz, 1 H),2.15-1.32 (m, 13 H), 0.97 (t, J = 7.3 Hz, 3 H). A, 2.22 318  83

¹H NMR (300 MHz, CDCl₃) δ 7.44-7.28 (m, 5 H), 6.93 (d, J = 3.0 Hz, 1 H),6.17 (d, J = 3.0 Hz, 4.95 (s, 1 H), 4.83 (s, 2 H), 4.78 (d, J = 5.2 Hz,2 H), 4.03 (t, J = 7.2 Hz, 2 H), 1.85-1.59 (m, 2 H), 1.35-1.10 (m, 2 H),0.84 (t, J = 7.3 Hz, 3 H). A, 2.55 296  84

¹H NMR (300 MHz, CDCl₃) δ 6.94 (d, J = 3.0 Hz, 1 H), 6.17 (d, J = 3.0Hz, 1 H), 5.08 (s, 2 H), 4.46 (s, 1 H), 4.27-3.99 (m, 2 H), 3.72 (d, J =6.9 Hz, 2 H), 8.12-−0.50 (m, 60 H), 2.71 (dd, J = 14.9, 7.4 Hz, 1 H),2.13-1.31 (m, 16 H), 0.92 (t, J = 6.8 Hz, 3 H). A, 2.65 332  85

¹H NMR (300 MHz, CDCl₃) δ 8.75 (d, J = 1.9 Hz, 1 H), 7.19 (s, J = 1.9Hz, 1 H), 7.02 (d, J = 3.0 Hz, 2 H), 6.19 (d, J = 3.0 Hz, 1 H), 5.36 (s,2 H), 5.22-4.88 (m, 2 H), 4.37 (s, 2 H), 3.48 (dd, J = 23.1, 14.8 Hz, 3H), 2.03-1.83 (m, 2 H), 1.81-1.05 (m, 5 H), 0.82 (dt, J = 19.4, 7.1 Hz,3 H). A, 1.35 347  86

¹H NMR (300 MHz, CDCl₃) δ 7.48-7.28 (m, 3 H), 7.15 (d, J = 6.8 Hz, 2 H),5.72 (d, J = 3.3 Hz, 1 H), 5.25 (s, 2 H), 4.44 (s, 2 H), 4.16 (s, 1 H),3.23 (dd, J = 12.0, 6.8 Hz, 2 H), 1.18 (dd, J = 14.4, 7.1 Hz, 2 H), 1.03(dd, J = 15.0, 7.1 Hz, 2 H), 0.79 (t, J = 7.1 Hz, 3 H). A, 2.58 314  87

¹H NMR (300 MHz, CDCl₃) δ 6.88 (d, J = 3.0 Hz, 1 H), 6.13 (d, J = 2.9Hz, 1 H), 5.60 (s, 1 H), 5.46 (s, 2 H), 4.57-4.45 (m, 1 H), 4.00 (dd, J= 15.0, 6.2 Hz, 1 H), 3.89-3.69 (m, 3 H), 2.10-1.91 (m, 2 H), 1.85-1.06(m, 16 H), 0.95 (dd, J = 15.9, 8.6 Hz, 3 H). A, 1.89 346  88

¹H NMR (300 MHz, CDCl₃) δ 8.79 (d, J = 1.9 Hz, 1 H), 7.19 (d, J = 1.6Hz, 1 H), 7.07 (s, 1 H), 6.25 (d, J = 8.1 Hz, 1 H), 6.22 (d, J = 3.0 Hz,1 H), 5.43 (d, J = 1.3 Hz, 2 H), 4.42 (s, 2 H), 4.34 (ddd, J = 11.0,5.5, 2.9 Hz, 1 H), 3.57 (dd, J = 11.8, 2.6 Hz, 1 H), 3.44 (td, J = 11.7,2.4 Hz, 2 H), 2.03-1.87 (m, 2 H), 1.70-1.45 (m, 2 H), 1.41-1.18 (m, 4H), 0.87 (t, J = 6.5 Hz, 3 H). A, 1.51 361  89

¹H NMR (300 MHz, CDCl₃) δ 9.55 (s, 1H), 8.34 (d, J = 4.5 Hz, 1 H), 7.70(td, J = 7.7, 1.7 Hz, 1 H), 7.30 (d, J = 7.8 Hz, 1 H), 7.23 (dd, J =7.0, 5.1 Hz, 1 H), 7.04 (d, J = 3.0 Hz, 1 H), 6.21 (d, J = 3.0 Hz, 1 H),5.92 (s, 3 H), 5.25 (s, 2 H), 4.75 (d, J = 5.5 Hz, 2 H), 2.32 (s, 3 H).A, 1.25 336  90

¹H NMR (300 MHz, CDCl₃) δ 9.39 (s, 1 H), 7.63 (t, J = 7.7 Hz, 1 H), 7.17(s, 1 H), 7.14 (d, J = 5.5 Hz, 1 H), 7.10 (d, J = 3.2 Hz, 1 H), 6.24 (d,J = 3.0 Hz, 1 H), 6.01 (s, 1 H), 5.33 (s, 2 H), 5.27 (s, 2 H), 4.83 (d,J = 5.6 Hz, 2 H), 2.39 (s, 3 H), 2.38 (s, 3 H). A, 1.37 350  91

¹H NMR (300 MHz, CDCl₃) δ 6.90 (d, J = 3.0 Hz, 1 H), 6.26 (d, J = 3.0Hz, 1 H), 5.49 (s, 1 H), 5.34 (d, J = 23.9 Hz, 2 H), 4.55-4.31 (m, 2 H),4.23 (s, 1 H), 4.09 (dd, J = 15.8, 4.2 Hz, 1 H), 3.85-3.49 (m, 4 H),2.15-1.81 (m, 6 H), 1.75-1.54 (m, 4 H), 1.54-1.30 (m, 3 H), 0.89 (dd, J= 14.3, 7.3 Hz, 3 H). A, 2.22 348  92

¹H NMR (300 MHz, CDCl₃) δ 6.70 (d, J = 2.9 Hz, 1 H), 6.06 (d, J = 3.0Hz, 1 H), 5.43 (s, 1 H), 5.31 (s, 2 H), 4.26 (t, J = 12.8 Hz, 2 H), 4.03(s, 1 H), 3.89 (dd, J = 15.8, 4.3 Hz, 1 H), 3.69-3.24 (m, 4 H),2.09-1.61 (m, 4 H), 1.60-1.33 (m, 4 H), 1.31-1.09 (m, 3 H), 0.74 (t, J =7.2 Hz, 3 H). A, 2.00 334  93

¹H NMR (300 MHz, CDCl₃) δ 7.37 (t, J = 7.4 Hz, 3 H), 7.08 (d, J = 6.6Hz, 2 H), 6.90 (d, J = 2.7 Hz, 1 H), 5.25 (s, 2 H), 4.53 (s, 2 H), 4.35(s, 1 H), 3.25 (dd, J = 12.1, 6.8 Hz, 2 H), 1.32-1.13 (m, 2 H), 1.04(dq, J = 13.9, 7.1 Hz, 2 H), 0.79 (t, J = 7.2 Hz, 3 H). A, 2.40 314  94

¹H NMR (300 MHz, CDCl₃) δ 7.38 (q, J = 6.2 Hz, 3 H), 7.07 (d, J = 6.5Hz, 2 H), 6.97 (d, J = 2.7 Hz, 1 H), 5.26 (d, J = 2.4 Hz, 2 H), 4.52 (s,2 H), 4.20 (d, J = 11.6 Hz, 1 H), 3.42 (d, J = 11.7 Hz, 1 H), 3.22 (td,J = 11.7, 2.4 Hz, 2 H), 1.85-1.66 (m, 2 H), 1.24 (d, J = 7.1 Hz, 2 H),0.95 (ddd, J = 24.8, 13.8, 9.0 Hz, 3 H), 0.75 (t, J = 6.8 Hz, 3 H). A,2.24 358  95

¹H NMR (300 MHz, CDCl₃) δ 7.46-7.31 (m, 3 H), 7.07 (d, J = 6.5 Hz, 2 H),6.97 (d, J = 2.7 Hz, 1 H), 5.26 (d, J = 3.3 Hz, 2 H), 4.55 (s, 2 H),4.32-4.02 (m, 1 H), 3.53-3.33 (m, 1 H), 3.22 (td, J = 11.7, 2.5 Hz, 2H), 1.74 (ddd, J = 14.3, 8.6, 4.1 Hz, 2 H), 1.38-1.08 (m, 3 H), 0.93(ddd, J = 13.8, 11.7, 4.3 Hz, 4 H), 0.80 (t, J = 7.2 Hz, 3 H). A, 2.44372  96

¹H NMR (300 MHz, CDCl₃) δ 7.49-7.30 (m, 3 H), 7.08 (d, J = 6.3 Hz, 2 H),6.91 (d, J = 2.7 Hz, 1 H), 5.24 (s, 2 H), 4.51 (s, 2 H), 4.28-3.96 (m, 1H), 1.08 (dddd, J = 18.0, 16.8, 13.6, 10.8 Hz, 7 H), 0.85 (d, J = 6.4Hz, 3 H), 0.77 (dd, J = 9.4, 4.5 Hz, 3 H). A, 2.55 328  97

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.94 (t, J = 7.4 Hz, 3 H), 1.29-1.47 (m,2 H), 1.61 (t, J = 7.1 Hz, 2 H), 3.46 (q, J = 6.7 Hz, 2 H), 3.80 (s, 6H), 5.17 (s, 2 H), 5.31 (s, 2 H), 5.80 (d, J = 2.9 Hz, 1 H), 6.33 (t, J= 5.4 Hz, 1 H), 6.66-6.83 (m, 3 H), 7.38 (t, J = 8.5 Hz, 1 H) A, 2.79356  98

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.91 (t, J = 7.29 Hz, 3 H) 1.14-1.43 (m,5 H) 1.46-1.72 (m, 2 H) 3.79 (s, 6 H) 4.41-4.60 (m, 1 H) 5.32-5.49 (m, 2H) 6.02 (d, J = 3.02 Hz, 1 H) 6.72-6.88 (m, 5 H) 6.92 (d, J = 3.02 Hz, 1H) 7.40 (t, J = 8.39 Hz, 1 H) A, 2.97 370  99

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.79-0.93 (m, 3 H) 1.18-1.39 (m, 4 H)1.49-1.86 (m, 4 H) 3.41-3.54 (m, 2 H) 3.78 (s, 6 H) 4.30-4.48 (m, 1 H)4.56-4.70 (m, 1 H) 5.10-5.24 (m, 2 H) 5.32 (s, 2 H) 5.78-5.83 (m, 1 H)5.85-5.93 (m, 1 H) 6.76 (s, 3 H) 7.30-7.44 (m, 1 H) A, 2.70 414 100

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.74-1.01 (m, 3 H) 1.19-1.44 (m, 2 H)1.46-1.74 (m, 2 H) 3.45-3.58 (m, 2 H) 3.80 (s, 6 H) 4.24-4.43 (m, 1 H)4.75-4.88 (m, 1 H) 5.11-5.22 (m, 2 H) 5.23-5.36 (m, 2 H) 5.74-5.81 (m, 1H) 5.81-5.85 (m, 1 H) 6.78 (s, 3 H) 7.29-7.44 (m, 1 H) A, 2.49 386 101

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.75-0.93 (m, 3 H) 1.19-1.40 (m, 4 H)1.45-1.61 (m, 1 H) 1.61-1.78 (m, 1 H) 3.44-3.63 (m, 2 H) 3.80 (s, 6 H)4.31 (d, J = 4.95 Hz, 1 H) 4.81 (br. s., 1 H) 5.17 (s, 2 H) 5.30 (s, 2H) 5.78 (d, J = 8.52 Hz, 1 H) 5.83 (d, J = 3.02 Hz, 1 H) 6.69-6.82 (m, 1H) 6.69-6.82 (m, 2 H) 7.37 (t, J = 8.39 Hz, 1 H) A, 2.69 400 102

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.89 (t, J = 7.40 Hz, 3 H) 1.20-1.42 (m,2 H) 1.44-1.85 (m, 4 H) 3.42-3.54 (m, 2 H) 3.78 (s, 6 H) 4.32-4.51 (m, 1H) 4.56-4.69 (m, 1 H) 5.12-5.23 (m, 2 H) 5.32 (s, 2 H) 5.81 (d, J = 2.90Hz, 1 H) 5.85-5.93 (m, 1 H) 6.71-6.79 (m, 3 H) 7.31-7.44 (m, 1 H) A,2.57 400 103

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.17 (s, 3 H) 3.31-3.42 (m, 3 H)3.45-3.56 (m, 3 H) 3.86 (s, 3 H) 5.11 (br. s., 2 H) 5.35 (s, 2 H) 5.62(t, J = 5.05 Hz, 1 H) 5.97 (d, J = 2.83 Hz, 1 H) 6.60-6.69 (m, 1 H) 6.84(td, J = 7.47, 0.81 Hz, 1 H) 7.05 (d, J = 8.07 Hz, 1 H) 7.18 (d, J =3.23 Hz, 1 H) 7.22-7.33 (m, 1 H) D, 0.74 328 104

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.56 (d, J = 6.87 Hz, 3 H) 4.01 (s, 3 H)5.26 (s, 2 H) 5.49 (t, J = 7.01 Hz, 1 H) 5.89 (d, J = 2.89 Hz, 1 H) 6.67(d, J = 7.42 Hz, 1 H) 7.14 (d, J = 2.89 Hz, 1 H) 7.28 (dd, J = 7.01,5.22 Hz, 1 H) 7.50 (d, J = 7.84 Hz, 1 H) 7.78 (td, J = 7.70, 1.65 Hz, 1H) 8.56 (d, J = 4.67 Hz, 1 H) A, 1.23 269 105

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.53 (d, J = 6.87 Hz, 3 H) 3.24 (s, 3 H)3.68 (t, J = 4.81 Hz, 2 H) 4.42 (t, J = 4.81 Hz, 2 H) 5.24 (s, 2 H) 5.47(t, J = 7.01 Hz, 1 H) 5.94 (d, J = 2.89 Hz, 1 H) 6.93 (d, J = 7.42 Hz, 1H) 7.20 (d, J = 3.02 Hz, 1 H) 7.26 (dd, J = 7.22, 5.02 Hz, 1 H) 7.47 (d,J = 7.84 Hz, 1 H) 7.75 (td, J = 7.63, 1.37 Hz, 1 H) 8.55 (d, J = 4.81Hz, 1 H) A, 1.45 313 106

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.95 (t, J = 7.37 Hz, 3 H) 1.37-1.46 (m,2 H) 1.64 (quin, J = 7.26 Hz, 2 H) 3.42 (td, J = 6.93, 5.28 Hz, 2 H)3.90 (s, 3 H) 5.18 (s, 2 H) 5.38 (s, 2 H) 5.89 (d, J = 3.08 Hz, 1 H)7.21 (d, J = 3.08 Hz, 1 H) 7.42 (dd, J = 8.47, 4.73 Hz, 1 H) 7.54-7.60(m, 2 H) 8.11 (dd, J = 4.73, 1.21 Hz, 1 H) D, 0.90 327 107

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.20 (s, 3 H) 3.36 (t, J = 6.05 Hz, 2 H)3.47-3.54 (m, 2 H) 3.71 (s, 3 H) 5.29 (s, 2 H) 5.42 (s, 2 H) 5.88 (t, J= 5.50 Hz, 1 H) 6.00 (d, J = 2.86 Hz, 1 H) 6.61 (d, J = 7.48 Hz, 1 H)6.63-6.66 (m, 1 H) 6.83 (dd, J = 8.14, 2.20 Hz, 1 H) 7.23 (t, J = 7.92Hz, 1 H) 7.35 (d, J = 3.08 Hz, 1 H) D, 0.71 328 108

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21 (d, J = 7.04 Hz, 6 H) 3.02 (m, J =6.60, 6.60, 6.60, 6.60, 6.60, 6.60 Hz, 0 H) 4.64 (d, J = 5.72 Hz, 2 H)5.35 (s, 2 H) 5.56 (s, 2 H) 5.97 (d, J = 3.08 Hz, 1 H) 6.01 (d, J = 0.66Hz, 1 H) 7.24 (t, J = 5.83 Hz, 1 H) 7.32 (d, J = 3.08 Hz, 1 H) 7.40 (d,J = 1.98 Hz, 1 H) 9.03 (d, J = 1.76 Hz, 1 H) D, 0.77 370 109

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.70 (t, J = 7.04 Hz, 3 H) 0.84-0.95 (m,2 H) 1.17-1.35 (m, 2 H) 1.38-1.46 (m, 1 H) 1.53-1.62 (m, 1 H) 3.23-3.34(m, 2 H) 3.68 (s, 3 H) 4.22 (dt, J = 8.53, 4.43 Hz, 1 H) 4.49 (t, J =5.50 Hz, 1 H) 5.14 (d, J = 8.58 Hz, 1 H) 5.23 (s, 2 H) 5.45 (q, J =16.95 Hz, 2 H) 5.98 (d, J = 2.86 Hz, 1 H) 6.48 (d, J = 7.70 Hz, 1 H)6.56-6.58 (m, 1 H) 6.82 (dd, J = 8.14, 2.20 Hz, 1 H) 7.21 (t, J = 7.92Hz, 1 H) 7.34 (d, J = 3.08 Hz, 1 H) D, 0.8  370 110

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.30 (s, 3 H) 3.80 (s, 3 H) 4.55 (d, J =5.72 Hz, 2 H) 5.34 (s, 2 H) 5.41 (s, 2 H) 5.71 (d, J = 0.88 Hz, 1 H)5.99 (d, J = 2.86 Hz, 1 H) 6.44 (dd, J = 7.59, 1.43 Hz, 1 H) 6.50 (t, J= 5.83 Hz, 1 H) 6.80 (td, J = 7.43, 0.99 Hz, 1 H) 7.01 (d, J = 7.48 Hz,1 H) 7.21-7.27 (m, 2 H) D, 0.79 365 111

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.59-1.70 (m, 4 H) 2.28-2.39 (m, 4 H)3.18 (s, 3 H) 3.32 (t, J = 6.46 Hz, 2 H) 3.44-3.50 (m, 4 H) 5.26 (s, 2H) 5.43 (s, 2 H) 5.86 (t, J = 4.84 Hz, 1 H) 5.97 (d, J = 2.83 Hz, 1 H)6.84-6.90 (m, 0 H) 7.03 (s, 1 H) 7.15 (m, J = 7.67 Hz, 1 H) 7.22 (t, J =7.30 Hz, 1 H) 7.32 (d, J = 3.23 Hz, 1 H) E, 1.18 381 112

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.29 (s, 3 H) 4.55 (d, J = 5.50 Hz, 2 H)5.55 (s, 1 H) 5.61 (s, 2 H) 5.68 (br. s., 2 H) 6.11 (d, J = 2.89 Hz, 1H) 6.83 (d, J = 5.64 Hz, 2 H) 6.92 (t, J = 5.43 Hz, 1 H) 7.43 (d, J =3.02 Hz, 1 H) 8.44 (d, J = 5.77 Hz, 2 H)  A, 0.994 336 113

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.60 (s, 3 H) 3.22 (s, 3 H) 3.52 (t, J =5.70 Hz, 2 H) 3.72 (q, J = 5.58 Hz, 2 H) 5.71 (br. s., 2 H) 6.26 (d, J =3.08 Hz, 1 H) 7.21 (d, J = 7.48 Hz, 1 H) 7.34-7.58 (m, 3 H) 7.72 (d, J =2.86 Hz, 1 H) 7.94 (t, J = 7.70 Hz, 1 H) 8.81-8.97 (m, 1 H) 12.60 (br.s., 1 H) E, 1.28 313 114

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.87 (t, J = 7.37 Hz, 3 H) 1.18-1.32 (m,2 H) 1.50 (quin, J = 7.21 Hz, 2 H) 3.33-3.38 (m, 2 H) 5.27 (s, 2 H) 5.79(s, 2 H) 5.99 (d, J = 3.08 Hz, 1 H) 6.47 (t, J = 5.28 Hz, 1 H) 7.35 (d,J = 2.86 Hz, 1 H) 7.67 (d, J = 3.08 Hz, 1 H) 7.77 (d, J = 3.30 Hz, 1 H)E, 1.6  303 115

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.30 (s, 3 H) 3.52-3.57 (m, 2 H)3.57-3.64 (m, 2 H) 3.90 (s, 3 H) 5.23 (s, 2 H) 5.37 (s, 2 H) 5.90 (d, J= 3.08 Hz, 1 H) 7.21 (d, J = 2.86 Hz, 1 H) 7.41 (dd, J = 8.36, 4.62 Hz,1 H) 7.54 (dd, J = 8.58, 1.10 Hz, 1 H) 7.80 (t, J = 4.95 Hz, 1 H) 8.12(dd, J = 4.73, 1.21 Hz, 1 H) D, 0.68 329 116

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.78 (t, J = 7.30 Hz, 3 H) 1.01-1.11 (m,2 H) 1.33 (quin, J = 7.26 Hz, 2 H) 1.62-1.68 (m, 4 H) 2.31-2.37 (m, 4 H)3.25-3.29 (m, 2 H) 3.48 (s, 2 H) 5.21 (s, 2 H) 5.47 (s, 2 H) 5.69 (t, J= 5.39 Hz, 1 H) 5.97 (d, J = 2.86 Hz, 1 H) 6.79 (d, J = 7.48 Hz, 1 H)7.01 (s, 1 H) 7.15 (d, J = 7.70 Hz, 1 H) 7.21 (t, J = 7.59 Hz, 1 H) 7.31(d, J = 2.86 Hz, 1 H) D, 0.73 379 117

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.15 (s, 3 H) 3.35 (t, J = 5.83 Hz, 2 H)3.50 (q, J = 5.65 Hz, 2 H) 5.30 (s, 2 H) 5.63 (s, 2 H) 6.01 (d, J = 3.08Hz, 1 H) 6.56 (t, J = 5.39 Hz, 1 H) 7.17 (d, J = 8.36 Hz, 1 H) 7.39 (d,J = 3.08 Hz, 1 H) 8.21 (dd, J = 8.36, 1.98 Hz, 1 H) 8.91-8.94 (m, 1 H)D, 0.77 367 118

¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.15 (s, 3 H) 3.25-3.31 (m, 2 H) 3.47(d, J = 5.77 Hz, 2 H) 5.32 (s, 2 H) 5.53 (s, 2 H) 5.97 (s, 1 H) 6.03 (d,J = 2.89 Hz, 1 H) 6.91 (d, J = 5.91 Hz, 2 H) 7.36 (d, J = 3.02 Hz, 1 H)8.47 (d, J = 5.91 Hz, 2 H) A, 0.83 299 119

¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.26 (s, 3 H) 3.44-3.52 (m, 2 H)3.52-3.62 (m, 2 H) 5.30 (s, 2 H) 5.44 (s, 2 H) 5.96 (d, J = 3.02 Hz, 1H) 7.29 (d, J = 7.70 Hz, 1 H) 7.33-7.45 (m, 1 H) 7.33-7.45 (m, 2 H) 7.83(td, J = 7.70, 1.65 Hz, 1 H) 8.56 (d, J = 4.26 Hz, 1 H) A, 0.83 299 120

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.25-3.29 (m, 3 H) 3.47-3.54 (m, 2 H)3.54-3.61 (m, 2 H) 3.81 (s, 3 H) 5.25 (s, 2 H) 5.33 (s, 2 H) 5.94 (d, J= 3.08 Hz, 1 H) 6.95 (dd, J = 5.72, 2.64 Hz, 1 H) 6.98 (d, J = 2.42 Hz,1 H) 7.39 (d, J = 3.08 Hz, 1 H) 7.74 (t, J = 5.06 Hz, 1 H) 8.37 (d, J =5.72 Hz, 1 H) D, 0.65 329 121

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.18 (s, 3 H) 3.38 (t, J = 5.70 Hz, 2 H)3.51 (q, J = 5.65 Hz, 2 H) 3.91 (s, 3 H) 5.31 (s, 2 H) 5.40 (s, 2 H)5.95-6.00 (m, 2 H) 7.08 (d, J = 5.72 Hz, 1 H) 7.21 (d, J = 3.08 Hz, 1 H)7.65 (s, 1 H) 8.38 (d, J = 5.72 Hz, 1 H) D, 0.52 329 122

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.28 (s, 3 H) 4.56 (d, J = 5.94 Hz, 2 H)5.38 (s, 2 H) 5.68 (s, 2 H) 5.76 (d, J = 0.88 Hz, 1 H) 6.05 (d, J = 3.08Hz, 1 H) 7.04 (d, J = 8.36 Hz, 1 H) 7.08 (t, J = 5.83 Hz, 1 H) 7.41 (d,J = 3.08 Hz, 1 H) 8.16 (dd, J = 8.36, 1.98 Hz, 1 H) 8.82-8.85 (m, 1 H)D, 0.80 404 123

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.31 (s, 3 H) 3.85 (s, 3 H) 4.56 (d, J =5.72 Hz, 2 H) 5.37 (s, 2 H) 5.44 (s, 2 H) 5.82 (s, 1 H) 6.01 (d, J =3.08 Hz, 1 H) 6.70 (t, J = 5.72 Hz, 1 H) 7.05 (d, J = 5.72 Hz, 1 H) 7.22(d, J = 2.86 Hz, 1 H) 7.53 (s, 1 H) 8.37 (d, J = 5.50 Hz, 1 H) D, 0.58366 124

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.31 (s, 3 H) 3.71 (s, 3 H) 3.72 (s, 3H) 4.60 (d, J = 5.72 Hz, 2 H) 5.32-5.37 (m, 4 H) 5.86 (s, 1 H) 5.99 (d,J = 2.86 Hz, 1 H) 6.55 (d, J = 7.92 Hz, 1 H) 6.83 (t, J = 5.83 Hz, 1 H)7.19 (d, J = 7.92 Hz, 1 H) 7.34 (d, J = 2.86 Hz, 1 H) D, 0.70 396 125

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.34 (s, 3 H) 4.63 (d, J = 5.50 Hz, 2 H)5.36 (s, 2 H) 5.58 (d, J = 1.76 Hz, 2 H) 5.97 (d, J = 3.08 Hz, 1 H) 6.06(d, J = 0.88 Hz, 1 H) 7.26 (dd, J = 3.08, 0.88 Hz, 1 H) 7.44-7.49 (m, 1H) 7.62 (t, J = 5.72 Hz, 1 H) 7.78 (ddd, J = 9.90, 8.47, 1.21 Hz, 1 H)8.21-8.24 (m, 1 H) D, 0.67 354 126

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.76-0.83 (m, 2 H) 0.99-1.04 (m, 2 H)2.06 (tt, J = 8.47, 4.95 Hz, 1 H) 4.59 (d, J = 5.50 Hz, 2 H) 5.36 (s, 2H) 5.48 (s, 2 H) 5.90 (s, 1 H) 5.99 (d, J = 2.86 Hz, 1 H) 7.14-7.17 (m,1 H) 7.31-7.35 (m, 1 H) 7.40 (d, J = 2.86 Hz, 1 H) 7.74 (t, J = 5.61 Hz,1 H) 7.76-7.82 (m, 1 H) 8.40-8.43 (m, 1 H) D, 0.74 362 127

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.19 (d, J = 7.04 Hz, 6 H) 2.94-3.08 (m,1 H) 4.63 (d, J = 5.72 Hz, 2 H) 5.37 (s, 2 H) 5.49 (s, 2 H) 5.93 (s, 1H) 5.99 (d, J = 3.08 Hz, 1 H) 7.15 (d, J = 7.92 Hz, 1 H) 7.32 (dd, J =7.04, 5.06 Hz, 1 H) 7.41 (d, J = 2.86 Hz, 1 H) 7.74 (t, J = 5.61 Hz, 1H) 7.78 (td, J = 7.70, 1.76 Hz, 1 H) 8.40 (d, J = 4.18 Hz, 1 H) D, 0.79364 128

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.35 (d, J = 0.66 Hz, 3 H) 3.15 (s, 3 H)3.55 (t, J = 5.06 Hz, 2 H) 4.36 (t, J = 4.95 Hz, 2 H) 4.62 (d, J = 5.72Hz, 2 H) 5.31 (s, 2 H) 5.92 (d, J = 3.08 Hz, 1 H) 6.18 (d, J = 0.88 Hz,1 H) 6.84 (t, J = 5.83 Hz, 1 H) 7.17 (d, J = 3.08 Hz, 1 H) E, 1.09 303129

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.38 (t, J = 6.9 Hz, 3 H), 3.15 (s, 3H), 3.27-3.33 (m, 2 H), 3.47 (q, J = 5.6 Hz, 2 H), 4.10 (q, J = 7.0 Hz,2 H), 5.29 (s, 26 H), 5.37 (s, 2 H), 5.72 (t, J = 5.4 Hz, 1 H), 5.97 (d,J = 2.9 Hz, 1 H), 6.59 (dd, J = 7.5, 1.5 Hz, 1 H), 6.79-6.85 (m, 1 H),7.02 (d, J = 7.7 Hz, 1 H), 7.20-7.27 (m, 2 H) E, 1.52 342 130

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.71-0.78 (m, 3 H), 0.96-1.08 (m, 2 H),1.28-1.38 (m, 2 H), 3.22-3.29 (m, 2 H), 5.28 (s, 2 H), 5.59 (s, 2 H),5.77 6 (t, J = 5.4 Hz, 1 H), 6.03 (d, J = 3.1 Hz, 1 H), 6.35 (d, J = 7.7Hz, 1 H), 7.19-7.25 (m, 1 H), 7.28 (d, J = 3.1 Hz, 1 H), 7.35-7.40 (m, 2H) SLAST_1343_1.1.esp E, 1.84 380 131

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.29-2.33 (m, 3 H) 3.71 (s, 3 H) 4.59(d, J = 5.72 Hz, 2 H) 5.36 (s, 2 H) 5.44 (s, 2 H) 5.82-5.85 (m, 1 H)6.01 (d, J = 3.08 Hz, 1 H) 6.50 (d, J = 7.26 Hz, 1 H) 6.70 (d, J = 8.14Hz, 1 H) 6.90 (t, J = 5.72 Hz, 1 H) 7.36 (d, J = 2.86 Hz, 1 H) 7.62 (dd,J = 8.25, 7.37 Hz, 1 H) D, 0.74 366 132

¹H NMR (300 MHz, chloroform-d) δ ppm 3.30 (s, 3 H) 3.47-3.60 (m, 2 H)3.68 (m, J = 5.10, 5.10, 5.10 Hz, 2 H) 5.37 (s, 2 H) 5.77 (br. s., 2 H)6.20 (d, J = 3.02 Hz, 1 H) 7.02 (d, J = 3.16 Hz, 1 H) 7.23-7.31 (m, 1 H)7.85 (br. s., 1 H) 8.78 (d, J = 1.79 Hz, 1 H) A, 1.61 305 133

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.79 (t, J = 7.3 Hz, 3 H), 1.09 (dq, J =15.0, 7.4 Hz, 2 H), 1.30-1.35 (m, 2 H), 1.38 (t, J = 6.9 Hz, 3 H),3.24-3.29 (m, 2 6 H), 4.10 (q, J = 6.9 Hz, 2 H), 5.22 (s, 2 H), 5.39 (s,2 H), 5.50 (t, J = 5.4 Hz, 1 H), 5.96 (d, J = 2.9 Hz, 1 H), 6.48 (dd, J= 7.5, 1.3 Hz, 1 H), 6.77-6.84 (m, 1 H), 7.03 (d, J = 7.9 Hz, 1 H),7.20-7.26 (m, 2 H) D, 1.0  340 134

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.91 (t, J = 7.4 Hz, 3 H), 1.29-1.39 (m,2 H), 1.54-1.65 (m, 2 H), 1.84-1.94 (m, 1 H), 2.17-2.30 (m, 1 H), 3.37-63.44 (m, 2 H), 3.70-3.79 (m, 2 H), 3.82 (s, 3 H), 3.83-3.90 (m, 2 H),4.97-5.04 (m, 1 H), 5.22 (s, 2 H), 5.30 (s, 2 H), 5.93 (d, J = 3.1 Hz, 1H), 7.03 (s, 1 H), 7.40 (d, J = 2.9 Hz, 1 H), 7.47 (t, J = 5.1 Hz, 1 H),8.10 (s, 1 H) D, 0.82 413 135

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.91 (t, J = 7.4 Hz, 3 H), 1.29-1.39 (m,2 H), 1.54-1.65 (m, 2 H), 1.84-1.94 (m, 1 H), 2.17-2.30 (m, 1 H), 3.37-63.44 (m, 2 H), 3.70-3.79 (m, 2 H), 3.82 (s, 3 H), 3.83-3.90 (m, 2 H),4.97-5.04 (m, 1 H), 5.22 (s, 2 H), 5.30 (s, 2 H), 5.93 (d, J = 3.1 Hz, 1H), 7.03 (s, 1 H), 7.40 (d, J = 2.9 Hz, 1 H), 7.47 (t, J = 5.1 Hz, 1 H),8.10 (s, 1 H) D, 0.64 415 136

¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.94 (d, J = 5.9 Hz, 2 H), 5.37 (s, 2H), 5.53 (s, 2 H), 6.01 (d, J = 3.1 Hz, 1 H), 7.15 (d, J = 7.7 Hz, 1 H),7.31 (ddd, J = 7.7, 6 4.8, 1.1 Hz, 1 H), 7.43 (d, J = 3.1 Hz, 1 H), 7.52(d, J = 3.3 Hz, 1 H), 7.71 (d, J = 3.3 Hz, 1 H), 7.78 (td, J = 7.7, 2.0Hz, 1 H), 8.10 (t, J = 5.8 Hz, 1 H), 8.42-8.46 (m, 1 H) D, 0.60 338 137

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05 (d, J = 6.2 Hz, 6 H), 3.46-3.59 (m,5 H), 5.27 (s, 2 H), 5.44 (s, 2 H), 5.96 (d, J = 3.1 Hz, 1 H), 7.17-7.25(m, 2 H), 6 7.31-7.39 (m, 2 H), 7.77-7.85 (m, 1 H), 8.51-8.59 (m, 1 H)D, 0.73 327 138

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.78 (quin, J = 6.6 Hz, 2 H), 3.20 (s, 3H), 3.28-3.32 (m, 2 H), 3.37-3.44 (m, 2 H), 5.25 (s, 2 H), 5.47 (s, 2H), 5.96 (d, 6 J = 2.9 Hz, 1 H), 7.01 (t, J = 5.2 Hz, 1 H), 7.16 (d, J =7.9 Hz, 1 H), 7.32-7.39 (m, 2 H), 7.81 (td, J = 7.7, 1.8 Hz, 1 H),8.53-8.56 (m, 1 H) D, 0.63 313 139

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.47-1.58 (m, 1 H), 1.72-1.88 (m, 3 H),3.39-3.54 (m, 2 H), 3.58-3.66 (m, 1 H), 3.70-3.78 (m, 1 H), 4.00 (quin,6 J = 6.2 Hz, 1 H), 5.26 (s, 2 H), 5.38-5.50 (m, 2 H), 5.96 (d, J = 2.9Hz, 1 H), 7.24 (d, J = 7.7 Hz, 1 H), 7.30 (t, J = 5.4 Hz, 1 H), 7.35(ddd, J = 7.6, 5.0, 1.1 Hz, 1 H), 7.39 (d, J = 3.1 Hz, 1 H), 7.82 (td, J= 7.7, 1.8 Hz, 1 H), 8.55 (ddd, J = 4.8, 1.5, 0.9 Hz, 1 H) D, 0.65 325140

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.08 (t, J = 7.0 Hz, 3 H), 3.43 (q, J =7.0 Hz, 2 H), 3.48-3.59 (m, 4 H), 5.27 (s, 2 H), 5.44 (s, 2 H), 5.96 (d,J = 3.1 Hz, 1 6 H), 7.23-7.31 (m, 2 H), 7.35 (ddd, J = 7.6, 5.0, 1.1 Hz,1 H), 7.38 (d, J = 3.1 Hz, 1 H), 7.81 (td, J = 7.7, 1.8 Hz, 1 H),8.53-8.57 (m, 1 H) D, 0.66 313 141

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.87 (t, J = 7.4 Hz, 3 H), 1.21-1.33 (m,1 H), 1.33-1.45 (m, 1 H), 3.26-3.33 (m, 1 H), 3.45 (dt, J = 13.1, 5.4Hz, 1 H), 6 3.50-3.60 (m, 1 H), 4.81 (br. s., 1 H), 5.27 (s, 2 H), 5.47(s, 2 H), 5.96 (d, J = 3.1 Hz, 1 H), 7.17-7.26 (m, 2 H), 7.34 (ddd, J =7.7, 4.8, 1.1 Hz, 1 H), 7.38 (d, J = 3.1 Hz, 1 H), 7.81 (td, J = 7.7,1.8 Hz, 1 H), 8.52-8.56 (m, 1 H) D, 0.58 313 142

¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.79 (d, J = 5.7 Hz, 2 H), 5.31 (s, 2H), 5.47 (s, 2 H), 5.99 (d, J = 2.9 Hz, 1 H), 7.14 (d, J = 0.7 Hz, 1 H),7.28-7.36 (m, 2 6 H), 7.42 (d, J = 2.9 Hz, 1 H), 7.81 (td, J = 7.7, 1.8Hz, 1 H), 7.99 (d, J = 0.9 Hz, 1 H), 8.06 (t, J = 5.6 Hz, 1 H),8.40-8.45 (m, 1 H) D, 0.57 322 143

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.23-2.32 (m, 3 H) 4.53 (d, J = 5.94 Hz,2 H) 5.40 (s, 2 H) 5.67-5.71 (m, 3 H) 6.07 (d, J = 3.08 Hz, 1 H) 6.90(d, J = 7.92 Hz, 1 H) 6.96 (t, J = 5.83 Hz, 1 H) 7.41 (d, J = 3.08 Hz, 1H) 7.81 (d, J = 7.70 Hz, 1 H) 8.01 (t, J = 7.92 Hz, 1 H) E, 1.43 404 144

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.31-2.35 (m, 3 H) 4.59 (d, J = 5.72 Hz,2 H) 5.36 (s, 2 H) 5.52 (s, 2 H) 5.89 (d, J = 0.88 Hz, 1 H) 6.00 (d, J =3.08 Hz, 1 H) 7.11 (dd, J = 8.69, 4.51 Hz, 1 H) 7.28 (t, J = 5.83 Hz, 1H) 7.39 (d, J = 3.08 Hz, 1 H) 7.70 (td, J = 8.80, 2.86 Hz, 1 H) 8.42 (d,J = 2.86 Hz, 1 H) E, 1.49 354 145

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.31 (d, J = 0.66 Hz, 3 H) 4.59 (d, J =5.72 Hz, 2 H) 5.38 (s, 2 H) 5.64 (s, 2 H) 5.84 (d, J = 0.66 Hz, 1 H)6.02 (d, J = 3.08 Hz, 1 H) 7.29 (t, J = 5.72 Hz, 1 H) 7.42-7.45 (m, 2 H)7.69-7.72 (m, 1 H) 8.71 (d, J = 5.06 Hz, 1 H) D, 0.79 404 146

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.93 (t, J = 7.3 Hz, 3 H), 1.37 (dq, J =15.0, 7.3 Hz, 2 H), 1.56-1.66 (m, 2 H), 2.21 (s, 3 H), 2.33 (s, 3 H),3.36-3.42 (m, 6 3 H), 3.72 (s, 3 H), 5.21 (s, 2 H), 5.44 (s, 2 H), 5.92(d, J = 3.1 Hz, 1 H), 7.30 (d, J = 3.1 Hz, 1 H), 7.85 (t, J = 5.1 Hz, 1H), 8.21 (s, 1 H) SLAST_1354_1.1.esp M07(s) E, 1.83 355 147

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.21 (s, 3 H), 2.34 (s, 3 H), 3.28 (s, 3H), 3.50-3.60 (m, 4 H), 3.72 (s, 3 H), 5.25 (s, 2 H), 5.42 (s, 2 H),5.92 (d, J = 3.16 Hz, 1 H), 7.31 (d, J = 2.9 Hz, 1 H), 8.14 (t, J = 4.7Hz, 1 H), 8.22 (s, 1 H) SLAST_1354_2.1.esp M04(m) E, 1.45 357 148

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.93 (t, J = 7.4 Hz, 3 H), 1.38 (dq, J =14.9, 7.4 Hz, 2 H), 1.47-1.67 (m, 4 H), 1.69-1.84 (m, 1 H), 1.85-1.99(m, 1 H), 6 3.34-3.42 (m, 2 H), 3.56-3.74 (m, 2 H), 4.01-4.11 (m, 1 H),4.17 (dd, J = 15.2, 6.2 Hz, 1 H), 4.37 (dd, J = 15.2, 2.9 Hz, 1 H), 5.26(s, 2 H), 5.91 (d, J = 3.1 Hz, 1 H), 6.51 (t, J = 5.2 Hz, 1 H), 7.14 (d,J = 2.9 Hz, 1 H) D, 0.81 290 149

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.83 (t, J = 7.4 Hz, 3 H), 1.17 (dq, J =14.9, 7.4 Hz, 2 H), 1.42 (quin, J = 7.3 Hz, 2 H), 3.21 (t, J = 8.7 Hz, 2H), 3.29-3.35 6 (m, 2 H), 4.60 (t, J = 8.7 Hz, 2 H), 5.23 (s, 2 H), 5.34(s, 2 H), 5.71 (t, J = 5.3 Hz, 1 H), 5.95 (d, J = 2.9 Hz, 1 H), 6.46 (d,J = 7.7 Hz, 1 H), 6.72 (t, J = 7.6 Hz, 1 H), 7.14 (d, J = 6.6 Hz, 1 H),7.23 (d, J = 3.1 Hz, 1 H) E, 1.72 338 150

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.16-3.24 (m, 5 H), 3.40 (t, J = 5.8 Hz,2 H), 3.52 (q, J = 5.6 Hz, 2 H), 4.60 (t, J = 8.7 Hz, 2 H), 5.28 (s, 2H), 5.31 (s, 2 6 H), 5.92 (t, J = 5.5 Hz, 1 H), 5.95 (d, J = 2.9 Hz, 1H), 6.58 (d, J = 7.5 Hz, 1 H), 6.73 (t, J = 7.5 Hz, 1 H), 7.14 (d, J =6.6 Hz, 1 H), 7.22 (d, J = 2.9 Hz, 1 H) E, 1.4  340 151

¹H NMR (400 MHz, chloroform-d) δ ppm 1.58 (d, J = 6.8 Hz, 3 H), 3.29 (s,3 H), 3.70-3.79 (m, 2 H), 4.32-4.41 (m, 2 H), 4.50 (br. s., 2 H), 5.49(t, J = 6.8 Hz, 1 H), 6.17 (d, J = 3.1 Hz, 1 H), 6.91 (d, J = 3.1 Hz, 1H), 7.14 (ddd, J = 7.5, 4.8, 1.1 Hz, 2 H), 7.33 (d, J = 7.7 Hz, 1 H),7.61 (td, J = 7.6, 1.8 Hz, 1 H), 8.50-8.60 (m, 1 H) E, 1.2  313 152

¹H NMR (400 MHz, chloroform-d) δ ppm 1.59 (d, J = 6.8 Hz, 3 H), 3.31 (s,3 H), 3.71-3.82 (m, 2 H), 4.39 (d, J = 5.1 Hz, 2 H), 4.42 (br. s., 2 H),5.50 (t, J = 6.7 Hz, 1 H), 6.18 (d, J = 2.9 Hz, 1 H), 6.93 (d, J = 3.1Hz, 1 H), 7.10-7.20 (m, 2 H), 7.35 (d, J = 7.9 Hz, 1 H), 7.63 (td, J =7.6, 1.8 Hz, 1 H), 8.53-8.60 (m, 1 H) E, 1.44 313 153

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.63 (dt, J = 6.66, 3.16 Hz, 4 H) 2.27(s, 3 H) 2.28-2.34 (m, 4 H) 3.44 (s, 2 H) 4.54 (d, J = 5.72 Hz, 2 H)5.32 (s, 2 H) 5.48 (s, 2 H) 5.56 (d, J = 0.88 Hz, 1 H) 6.01 (d, J = 2.86Hz, 1 H) 6.61 (t, J = 5.94 Hz, 1 H) 6.76 (d, J = 7.26 Hz, 1 H) 6.98 (s,1 H) 7.12-7.20 (m, 2 H) 7.35 (d, J = 2.86 Hz, 1 H) E, 1.07 418 154

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.34 (s, 3 H) 4.62 (d, J = 5.72 Hz, 2 H)5.34 (s, 2 H) 5.55 (s, 2 H) 5.97 (d, J = 3.08 Hz, 1 H) 6.02 (s, 1 H)7.28 (t, J = 5.83 Hz, 1 H) 7.32 (d, J = 2.86 Hz, 1 H) 7.40 (d, J = 1.98Hz, 1 H) 9.04 (d, J = 1.98 Hz, 1 H) E, 1.14 342 155

¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.70 (d, J = 5.72 Hz, 2 H) 5.37 (s, 2 H)5.48 (s, 2 H) 5.98 (d, J = 3.08 Hz, 1 H) 6.38 (d, J = 1.76 Hz, 1 H) 7.20(d, J = 7.70 Hz, 1 H) 7.32 (ddd, J = 7.54, 5.01, 1.10 Hz, 1 H) 7.41 (d,J = 3.08 Hz, 1 H) 7.79 (td, J = 7.70, 1.76 Hz, 1 H) 7.87 (t, J = 5.61Hz, 1 H) 8.39-8.42 (m, 1 H) 8.77 (d, J = 1.76 Hz, 1 H) E, 1.34 322 156

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.34 (d, J = 0.66 Hz, 3 H) 4.62 (d, J =5.50 Hz, 2 H) 5.36 (s, 2 H) 5.62 (s, 2 H) 5.97 (d, J = 3.08 Hz, 1 H)6.03 (d, J = 0.66 Hz, 1 H) 7.29 (d, J = 3.08 Hz, 1 H) 7.42 (dd, J =8.14, 4.84 Hz, 1 H) 7.68 (t, J = 5.72 Hz, 1 H) 8.00 (dd, J = 8.14, 1.54Hz, 1 H) 8.32 (dd, J = 4.73, 1.43 Hz, 1 H) D, 0.74 370 157

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.27 (s, 3 H) 4.68 (d, J = 5.72 Hz, 2 H)5.33 (s, 2 H) 5.48 (s, 2 H) 5.94 (d, J = 2.86 Hz, 1 H) 6.01 (s, 1 H)6.89 (td, J = 6.77, 1.21 Hz, 1 H) 7.26 (ddd, J = 9.08, 6.66, 1.21 Hz, 1H) 7.35-7.38 (m, 2 H) 7.79 (s, 1 H) 8.30 (t, J = 5.72 Hz, 1 H) 8.51 (dt,J = 6.82, 1.10 Hz, 1 H) D, 0.65 375 158

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.33 (s, 3 H) 4.60 (d, J = 5.72 Hz, 2 H)5.38 (s, 2 H) 5.52 (s, 2 H) 5.89 (s, 1 H) 6.01 (d, J = 3.08 Hz, 1 H)7.18-7.22 (m, 1 H) 7.39-7.50 (m, 3 H) 8.41 (d, J = 5.50 Hz, 1 H) E, 1.35370 159

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.31 (s, 3 H) 4.56 (d, J = 5.72 Hz, 2 H)5.39 (s, 2 H) 5.56 (s, 2 H) 5.75 (s, 1 H) 6.05 (d, J = 3.08 Hz, 1 H)6.68 (d, J = 7.48 Hz, 1 H) 6.99 (t, J = 5.83 Hz, 1 H) 7.38 (d, J = 2.86Hz, 1 H) 7.41 (d, J = 7.92 Hz, 1 H) 7.78 (t, J = 7.81 Hz, 1 H) D, 0.73370 160

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46-1.70 (m, 2 H), 1.70-1.83 (m, 1 H),1.87-1.99 (m, 1 H), 3.29 (s, 3 H), 3.48-3.56 (m, 3 H), 3.56-3.65 (m, 2H), 6 3.68-3.77 (m, 1 H), 4.05 (qd, J = 6.7, 2.8 Hz, 1 H), 4.14 (dd, J =15.1, 6.5 Hz, 1 H), 4.35 (dd, J = 15.1, 2.8 Hz, 1 H), 5.23 (s, 2 H),5.92 (d, J = 2.9 Hz, 1 H), 6.61 (t, J = 4.8 Hz, 1 H), 7.15 (d, J = 3.1Hz, 1 H) D, 0.58 292 161

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.76 (t, J = 7.3 Hz, 3 H), 1.05 (dq, J =15.0, 7.3 Hz, 2 H), 1.30-1.40 (m, 2 H), 3.24-3.30 (m, 2 H), 5.26 (s, 2H), 5.51 (s, 6 2 H), 5.70 (t, J = 5.5 Hz, 1 H), 6.00 (d, J = 2.9 Hz, 1H), 6.36-6.41 (m, 1 H), 7.06-7.12 (m, 1 H), 7.20-7.25 (m, 2 H), 7.29 (t,J = 73.8 Hz, 1 H), 7.30-7.36 (m, 1 H) D, 0.94 362 162

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.13 (s, 3 H), 3.32-3.35 (m, 2 H), 3.46(q, J = 5.6 Hz, 2 H), 5.32 (s, 2 H), 5.48 (s, 2 H), 5.80 (t, J = 5.4 Hz,1 H), 6.01 (d, 6 J = 3.1 Hz, 1 H), 6.51 (dd, J = 7.7, 1.3 Hz, 1 H),7.08- 7.14 (m, 1 H), 7.20-7.25 (m, 2 H), 7.28 (t, J = 73.8 Hz, 1 H),7.31-7.36 (m, 1 H) D, 0.78 364 163

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80 (t, J = 7.3 Hz, 3 H), 1.12 (dq, J =15.0, 7.4 Hz, 2 H), 1.34-1.44 (m, 2 H), 3.26-3.31 (m, 2 H), 4.23-4.30(m, 2 H), 6 4.30-4.37 (m, 2 H), 5.24 (s, 2 H), 5.38 (s, 2 H), 5.59 (t, J= 5.4 Hz, 1 H), 5.96 (d, J = 3.1 Hz, 1 H), 6.02 (dd, J = 7.6, 1.4 Hz, 1H), 6.68 (t, J = 7.8 Hz, 1 H), 6.77 (dd, J = 8.1, 1.5 Hz, 1 H), 7.20 (d,J = 2.9 Hz, 1 H) D, 0.9  354 164

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.16 (s, 3 H), 3.35-3.40 (m, 2 H), 3.51(q, J = 5.6 Hz, 2 H), 4.24-4.31 (m, 2 H), 4.31-4.37 (m, 2 H), 5.35 (s, 2H), 6 5.37 (br. s., 2 H), 5.78 (t, J = 5.4 Hz, 1 H), 5.97 (d, J = 3.1Hz, 1 H), 6.16 (dd, J = 7.7, 1.5 Hz, 1 H), 6.70 (t, J = 7.8 Hz, 1 H),6.76-6.81 (m, 1 H), 7.22 (d, J = 2.9 Hz, 1 H) D, 0.74 356 165

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.16 (s, 3 H), 3.35-3.40 (m, 2 H), 3.51(q, J = 5.6 Hz, 2 H), 4.24-4.31 (m, 2 H), 4.31-4.37 (m, 2 H), 5.35 (s, 2H), 6 5.37 (br. s., 2 H), 5.78 (t, J = 5.4 Hz, 1 H), 5.97 (d, J = 3.1Hz, 1 H), 6.16 (dd, J = 7.7, 1.5 Hz, 1 H), 6.70 (t, J = 7.8 Hz, 1 H),6.76-6.81 (m, 1 H), 7.22 (d, J = 2.9 Hz, 1 H) D, 0.6  277 166

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.92 (t, J = 7.4 Hz, 3 H), 1.37 (dq, J =15.0, 7.3 Hz, 2 H), 1.51-1.62 (m, 2 H), 2.63 (d, J = 4.6 Hz, 3 H),3.33-3.41 (m, 2 6 H), 4.74 (s, 2 H), 5.40 (br. s., 2 H), 5.94 (d, J =2.9 Hz, 1 H), 6.93 (t, J = 5.2 Hz, 1 H), 7.11 (d, J = 3.1 Hz, 1 H), 8.31(d, J = 4.4 Hz, 1 H) D, 0.42 293 167

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.34 (s, 3 H) 3.78 (s, 3 H) 4.63 (d, J =5.50 Hz, 2 H) 5.33-5.39 (m, 4 H) 5.97 (d, J = 3.08 Hz, 1 H) 6.02 (s, 1H) 6.90 (d, J = 2.42 Hz, 1 H) 6.93 (dd, J = 5.72, 2.42 Hz, 1 H) 7.41 (d,J = 3.08 Hz, 1 H) 8.16 (t, J = 5.61 Hz, 1 H) 8.22 (d, J = 5.94 Hz, 1 H)D, 0.7  366 168

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.36 (s, 3 H) 3.79 (s, 3 H) 3.88 (s, 3H) 4.66 (d, J = 5.50 Hz, 2 H) 5.33 (s, 2 H) 5.36 (s, 2 H) 5.94 (d, J =2.86 Hz, 1 H) 6.18 (s, 1 H) 7.14 (d, J = 5.72 Hz, 1 H) 7.23 (d, J = 3.08Hz, 1 H) 8.00 (d, J = 5.50 Hz, 1 H) 8.50 (t, J = 5.50 Hz, 1 H) E, 1.62396 169

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.17 (s, 3 H) 2.31 (s, 3 H) 2.35 (s, 3H) 3.71 (s, 3 H) 4.63 (d, J = 5.50 Hz, 2 H) 5.32 (s, 2 H) 5.44 (s, 2 H)5.94 (d, J = 3.08 Hz, 1 H) 6.10 (s, 1 H) 7.33 (d, J = 2.86 Hz, 1 H) 8.01(s, 1 H) 8.49 (t, J = 5.50 Hz, 1 H) E, 1.76 394 170

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.35 (s, 3 H) 3.88 (s, 3 H) 4.66 (d, J =5.50 Hz, 2 H) 5.33 (s, 2 H) 5.40 (s, 2 H) 5.93 (d, J = 2.86 Hz, 1 H)6.13 (s, 1 H) 7.23 (d, J = 3.08 Hz, 1 H) 7.38 (dd, J = 8.36, 4.62 Hz, 1H) 7.52 (d, J = 7.92 Hz, 1 H) 7.92 (dd, J = 4.62, 1.10 Hz, 1 H) 8.19 (t,J = 5.50 Hz, 1 H) E, 1.59 366 171

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.33 (s, 3 H) 3.79 (s, 3 H) 4.63 (d, J =5.50 Hz, 2 H) 5.34 (s, 2 H) 5.40 (s, 2 H) 5.96 (d, J = 2.86 Hz, 1 H)5.98 (d, J = 0.88 Hz, 1 H) 7.20 (d, J = 8.58 Hz, 1 H) 7.37-7.41 (m, 2 H)7.79 (t, J = 5.72 Hz, 1 H) 8.09 (d, J = 2.64 Hz, 1 H) E, 1.53 366 172

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.27 (s, 3 H) 4.56 (d, J = 5.72 Hz, 2 H)5.35 (s, 2 H) 5.59-5.64 (m, 3 H) 6.04 (d, J = 3.08 Hz, 1 H) 6.84 (t, J =5.83 Hz, 1 H) 7.03 (dd, J = 6.05, 2.75 Hz, 1 H) 7.45 (d, J = 2.86 Hz, 1H) 7.65 (br. s., 1 H) 7.80 (br. s., 1 H) 7.86-7.92 (m, 2 H) E, 1.1  379173

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.55 (s, 3 H) 4.76 (d, J = 5.50 Hz, 2 H)5.30 (s, 2 H) 5.46 (s, 2 H) 5.98 (d, J = 2.86 Hz, 1 H) 7.31-7.36 (m, 2H) 7.42 (d, J = 3.08 Hz, 1 H) 7.81 (td, J = 7.70, 1.76 Hz, 1 H) 8.06 (t,J = 5.61 Hz, 1 H) 8.44-8.47 (m, 1 H) E, 1.34 337 174

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.63 (s, 3 H) 4.67 (d, J = 5.28 Hz, 2 H)5.32 (s, 2 H) 5.49 (s, 2 H) 5.98 (d, J = 2.86 Hz, 1 H) 7.02 (s, 1 H)7.23 (d, J = 7.70 Hz, 1 H) 7.33 (dd, J = 6.93, 5.17 Hz, 1 H) 7.40 (d, J= 3.08 Hz, 1 H) 7.75-7.83 (m, 2 H) 8.43 (d, J = 4.40 Hz, 1 H) D, 0.66352 175

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.25 (s, 3 H) 2.34 (s, 3 H) 4.62 (d, J =5.50 Hz, 2 H) 5.34 (s, 2 H) 5.42 (s, 2 H) 5.96-5.99 (m, 2 H) 7.12 (d, J= 7.92 Hz, 1 H) 7.39 (d, J = 2.86 Hz, 1 H) 7.60 (dd, J = 8.03, 2.09 Hz,1 H) 7.84 (t, J = 5.61 Hz, 1 H) 8.22-8.25 (m, 1 H) D, 0.72 350 176

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.22 (s, 3 H) 4.67 (d, J = 5.72 Hz, 2 H)5.35 (s, 2 H) 5.63 (s, 2 H) 5.98 (d, J = 3.08 Hz, 1 H) 6.07-6.09 (m, 1H) 7.07 (t, J = 5.83 Hz, 1 H) 7.34 (d, J = 3.08 Hz, 1 H) 7.46-7.51 (m, 1H) 7.55-7.61 (m, 2 H) 7.79-7.84 (m, 2 H) 8.57 (s, 1 H) E, 1.35 402 177

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.25 (s, 3 H) 2.32 (s, 3 H) 4.37 (d, J =5.06 Hz, 2 H) 5.26 (s, 2 H) 5.40 (s, 2 H) 5.95 (d, J = 3.08 Hz, 1 H)7.31-7.37 (m, 2 H) 7.39 (d, J = 3.08 Hz, 1 H) 7.77-7.82 (m, 2 H)8.45-8.48 (m, 1 H) E, 1.23 350 178

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.30 (s, 3 H) 4.56 (d, J = 5.72 Hz, 2 H)5.38 (s, 2 H) 5.54 (s, 2 H) 5.75-5.80 (m, 1 H) 6.04 (d, J = 2.86 Hz, 1H) 6.66 (dd, J = 7.37, 2.31 Hz, 1 H) 6.87 (t, J = 5.83 Hz, 1 H) 7.06(dd, J = 8.14, 2.20 Hz, 1 H) 7.36 (d, J = 2.86 Hz, 1 H) 7.85-7.92 (m, 1H) F, 4   354 179

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.30 (s, 3 H) 3.90 (s, 3 H) 4.53 (d, J =5.72 Hz, 2 H) 5.38 (s, 2 H) 5.42 (s, 2 H) 5.72 (s, 1 H) 6.03 (d, J =3.08 Hz, 1 H) 6.60-6.65 (m, 2 H) 6.84 (dd, J = 7.26, 5.06 Hz, 1 H) 7.27(d, J = 2.86 Hz, 1 H) 8.05 (dd, J = 4.95, 1.65 Hz, 1 H) E, 1.27 366 180

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.31 (s, 3 H) 3.69 (s, 6 H) 4.58 (d, J =5.50 Hz, 2 H) 5.33 (s, 2 H) 5.43 (s, 2 H) 5.92 (s, 1 H) 5.99 (d, J =2.64 Hz, 1 H) 6.11 (s, 1 H) 6.80 (t, J = 5.61 Hz, 1 H) 7.27 (d, J = 2.64Hz, 1 H) E, 1.34 397 181

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.30 (s, 3 H) 2.34 (s, 3 H) 4.61 (d, J =5.72 Hz, 2 H) 5.38 (s, 2 H) 5.52 (s, 2 H) 5.83 (s, 1 H) 6.00 (d, J =3.08 Hz, 1 H) 6.04 (s, 1 H) 6.85 (t, J = 5.72 Hz, 1 H) 7.29 (d, J = 3.08Hz, 1 H) E, 1.17 340 182

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.20 (s, 3 H) 4.63 (d, J = 5.72 Hz, 2 H)5.34 (s, 2 H) 5.64 (s, 2 H) 5.82 (s, 1 H) 6.01 (d, J = 3.08 Hz, 1 H)7.45 (d, J = 3.08 Hz, 1 H) 7.58 (s, 1 H) 7.66-7.70 (m, 1 H) 7.75-7.80(m, 2 H) 7.85-7.89 (m, 1 H) 8.13 (d, J = 8.14 Hz, 1 H) 9.20 (s, 1 H) E,1.47 386 183

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.07 (s, 1 H) 2.14 (s, 3 H) 4.57 (d, J =5.72 Hz, 2 H) 5.35 (s, 1 H) 5.77-5.82 (m, 3 H) 6.06 (d, J = 2.86 Hz, 1H) 7.18 (d, J = 8.36 Hz, 1 H) 7.51 (d, J = 2.86 Hz, 1 H) 7.56 (t, J =5.72 Hz, 1 H) 7.64 (dd, J = 8.14, 4.18 Hz, 1 H) 8.45 (d, J = 8.36 Hz, 2H) 9.09 (dd, J = 4.07, 1.65 Hz, 1 H) E, 1.03 387 184

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.16 (s, 3 H) 4.71 (d, J = 5.50 Hz, 2 H)5.37 (s, 2 H) 5.50 (s, 2 H) 5.95 (s, 1 H) 5.99 (d, J = 2.86 Hz, 1 H)7.18 (d, J = 7.70 Hz, 1 H) 7.35 (dd, J = 6.82, 5.06 Hz, 1 H) 7.42 (d, J= 3.08 Hz, 1 H) 7.81 (td, J = 7.65, 1.65 Hz, 1 H) 7.88 (t, J = 5.50 Hz,1 H) 8.47 (d, J = 4.40 Hz, 1 H) E, 1.11 336 185

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.34 (s, 3 H) 2.42 (s, 3 H) 4.63 (d, J =5.72 Hz, 2 H) 5.34 (s, 2 H) 5.49 (s, 2 H) 5.95 (d, J = 2.86 Hz, 1 H)6.07 (s, 1 H) 7.27 (dd, J = 7.70, 4.84 Hz, 1 H) 7.32 (d, J = 3.08 Hz, 1H) 7.66 (d, J = 7.48 Hz, 1 H) 8.17 (dd, J = 4.73, 0.99 Hz, 1 H) 8.35 (t,J = 5.61 Hz, 1 H) E, 1.35 350 186

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.31-2.36 (m, 3 H) 4.58 (d, J = 5.72 Hz,2 H) 5.34 (s, 2 H) 5.62 (s, 2 H) 5.93 (d, J = 0.66 Hz, 1 H) 5.97 (d, J =3.08 Hz, 1 H) 7.13 (t, J = 5.61 Hz, 1 H) 7.30 (d, J = 3.08 Hz, 1 H) 7.43(t, J = 4.95 Hz, 1 H) 8.72 (d, J = 5.06 Hz, 2 H) E, 0.98 337 187

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.17 (s, 3 H) 3.65 (s, 3 H) 4.46 (d, J =5.28 Hz, 2 H) 5.29 (s, 2 H) 5.44 (s, 2 H) 5.76 (s, 1 H) 5.96 (d, J =3.08 Hz, 1 H) 7.20 (d, J = 7.92 Hz, 1 H) 7.30-7.34 (m, 1 H) 7.38 (d, J =3.08 Hz, 1 H) 7.51 (t, J = 5.28 Hz, 1 H) 7.78 (td, J = 7.70, 1.76 Hz, 1H) 8.39 (d, J = 4.18 Hz, 1 H) E, 1.16 349 188

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.57 (s, 3 H) 4.45 (d, J = 5.06 Hz, 2 H)5.34 (br. s., 2 H) 5.44 (s, 2 H) 5.97 (d, J = 2.86 Hz, 1 H) 6.76 (s, 1H) 7.24 (d, J = 7.70 Hz, 1 H) 7.33 (dd, J = 7.04, 5.28 Hz, 1 H) 7.39 (d,J = 2.86 Hz, 1 H) 7.47 (s, 1 H) 7.64 (t, J = 4.84 Hz, 1 H) 7.77-7.83 (m,1 H) 8.43 (d, J = 4.40 Hz, 1 H) E, 0.92 335 189

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.25 (s, 3 H) 4.67 (d, J = 5.50 Hz, 2 H)5.26 (s, 2 H) 5.54 (s, 2 H) 5.99 (d, J = 2.86 Hz, 1 H) 6.97 (d, J = 7.92Hz, 1 H) 7.13 (d, J = 7.92 Hz, 1 H) 7.32 (ddd, J = 6.93, 5.61, 0.88 Hz,1 H) 7.41 (d, J = 3.08 Hz, 1 H) 7.43 (dd, J = 8.14, 1.98 Hz, 1 H) 7.62(t, J = 5.61 Hz, 1 H) 7.79 (td, J = 7.70, 1.76 Hz, 1 H) 8.30- 8.32 (m, 1H) 8.43 (dd, J = 4.95, 0.77 Hz, 1 H) E, 1.27 346 190

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.52 (d, J = 6.82 Hz, 3 H) 5.21 (s, 2 H)5.43 (quin, J = 6.82 Hz, 1 H) 5.48-5.60 (m, 2 H) 5.97 (d, J = 2.86 Hz, 1H) 7.18-7.25 (m, 1 H) 7.27-7.39 (m, 3 H) 7.44 (d, J = 2.86 Hz, 1 H)7.63-7.69 (m, 1 H) 7.76 (d, J = 7.26 Hz, 1 H) 7.80-7.88 (m, 1 H)8.46-8.52 (m, 2 H) E, 1.31 346 191

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.23 (d, J = 1.10 Hz, 3 H) 4.72 (d, J =5.50 Hz, 2 H) 5.31 (s, 2 H) 5.47 (s, 2 H) 5.98 (d, J = 2.86 Hz, 1 H)6.73 (d, J = 1.10 Hz, 1 H) 7.28-7.36 (m, 2 H) 7.42 (d, J = 3.08 Hz, 1 H)7.81 (td, J = 7.70, 1.76 Hz, 1 H) 7.99 (t, J = 5.50 Hz, 1 H) 8.40-8.44(m, 1 H) E, 1.11 336 192

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.34 (d, J = 0.7 Hz, 3 H), 2.53 (s, 3H), 4.64 (d, J = 5.7 Hz, 2 H), 5.35 (s, 2 H), 5.41 (s, 2 H), 5.95 (d, J= 3.1 Hz, 1 H), 6 6.08 (d, J = 0.7 Hz, 1 H), 7.27 (s, 1 H), 7.31 (d, J =3.1 Hz, 1 H), 7.57 (t, J = 5.7 Hz, 1 H) D, 0.7  356 193

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.98 (s, 3 H) 4.62 (d, J = 5.28 Hz, 2 H)5.36 (s, 2 H) 5.44 (s, 2 H) 5.96 (d, J = 2.86 Hz, 1 H) 7.25 (d, J = 7.70Hz, 1 H) 7.31-7.35 (m, 1 H) 7.38 (d, J = 3.08 Hz, 1 H) 7.77-7.83 (m, 2H) 7.89 (t, J = 5.39 Hz, 1 H) 8.41 (dd, J = 4.84, 0.66 Hz, 1 H) E, 0.93336 194

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.52 (d, J = 7.04 Hz, 3 H) 5.21 (s, 2 H)5.43 (quin, J = 7.04 Hz, 1 H) 5.47-5.58 (m, 2 H) 5.97 (d, J = 2.86 Hz, 1H) 7.19-7.23 (m, 1 H) 7.28-7.38 (m, 3 H) 7.44 (d, J = 3.08 Hz, 1 H) 7.66(td, J = 7.70, 1.76 Hz, 1 H) 7.76 (d, J = 7.26 Hz, 1 H) 7.84 (td, J =7.70, 1.76 Hz, 1 H) 8.47-8.51 (m, 2 H). E, 1.27 346 195

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.52 (d, J = 6.82 Hz, 3 H) 5.21 (s, 2 H)5.42 (quin, J = 6.99 Hz, 1 H) 5.47-5.58 (m, 2 H) 5.97 (d, J = 2.86 Hz, 1H) 7.19-7.23 (m, 1 H) 7.28-7.38 (m, 3 H) 7.44 (d, J = 3.08 Hz, 1 H) 7.66(td, J = 7.65, 1.65 Hz, 1 H) 7.77 (d, J = 7.26 Hz, 1 H) 7.84 (td, J =7.59, 1.32 Hz, 1 H) 8.47-8.51 (m, 2 H) E, 1.27 346 196

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.56 (s, 3 H) 3.90 (s, 3 H) 4.81 (d, J =5.72 Hz, 2 H) 5.27 (s, 2 H) 5.40 (s, 2 H) 5.93 (d, J = 3.08 Hz, 1 H)7.25 (d, J = 3.08 Hz, 1 H) 7.40 (dd, J = 8.36, 4.84 Hz, 1 H) 7.52-7.56(m, 1 H) 7.98 (dd, J = 4.84, 1.10 Hz, 1 H) 8.41 (t, J = 5.50 Hz, 1 H) E,1.24 367 197

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55 (d, J = 7.0 Hz, 3 H), 2.58 (s, 3H), 5.22 (s, 2 H), 5.41-5.49 (m, 1 H), 5.46 (d, J = 6.8 Hz, 2 H), 5.94(d, J = 3.1 Hz, 1 6 H), 7.23 (ddd, J = 7.5, 4.8, 0.9 Hz, 1 H), 7.34 (d,J = 3.1 Hz, 1 H), 7.38 (d, J = 8.1 Hz, 1 H), 7.40 (s, 1 H), 7.47 (d, J =7.5 Hz, 1 H), 7.69 (td, J = 7.7, 1.8 Hz, 1 H), 8.47-8.54 (m, 1 H) E,1.37 366 198

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15 (s, 6 H) 1.69-1.74 (m, 2 H)3.57-3.64 (m, 2 H) 5.62 (s, 2 H) 6.22 (d, J = 2.86 Hz, 1 H) 7.34-7.48(m, 4 H) 7.67 (d, J = 3.08 Hz, 1 H) 7.91 (td, J = 7.70, 1.76 Hz, 1 H)8.56-8.59 (m, 1 H) 8.79 (t, J = 4.80 Hz, 1 H) 12.51 (br. s., 1 H) E,1.09 327 199

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21 (d, J = 7.04 Hz, 6 H) 2.97-3.10 (m,1 H) 3.14-3.18 (m, 3 H) 3.56 (t, J = 4.95 Hz, 2 H) 4.37 (t, J = 5.06 Hz,2 H) 4.65 (d, J = 5.72 Hz, 2 H) 5.37 (s, 2 H) 5.93 (d, J = 3.08 Hz, 1 H)6.18 (s, 1 H) 6.86 (t, J = 5.61 Hz, 1 H) 7.17 (d, J = 3.08 Hz, 1 H) D,0.74 331 200

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.78-0.90 (m, 2 H) 0.94-1.06 (m, 2 H)2.03- 2.17 (m, 1 H) 3.11-3.18 (m, 3 H) 3.55 (t, J = 5.06 Hz, 2 H) 4.36(t, J = 5.06 Hz, 2 H) 4.61 (d, J = 5.72 Hz, 2 H) 5.36 (s, 2 H) 5.92 (d,J = 3.08 Hz, 1 H) 6.15 (s, 1 H) 6.84 (t, J = 5.72 Hz, 1 H) 7.17 (d, J =3.08 Hz, 1 H) D, 0.69 329 201

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54 (d, J = 7.04 Hz, 3 H) 3.20 (s, 3 H)3.63 (dt, J = 5.94, 3.19 Hz, 2 H) 4.32-4.50 (m, 2 H) 5.23 (s, 2 H) 5.42(t, J = 7.04 Hz, 1 H) 5.92 (d, J = 2.86 Hz, 1 H) 6.68 (d, J = 7.04 Hz, 1H) 7.18 (d, J = 3.08 Hz, 1 H) 7.34 (ddd, J = 7.87, 4.68, 0.66 Hz, 1 H)7.84 (dt, J = 7.92, 1.76 Hz, 1 H) 8.42 (dd, J = 4.62, 1.54 Hz, 1 H) 8.68(d, J = 2.20 Hz, 1 H) D, 0.6 313 202

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.27 (s, 3 H) 3.17-3.19 (m, 3 H) 3.61(t, J = 5.06 Hz, 2 H) 4.40 (t, J = 5.06 Hz, 2 H) 4.70 (d, J = 5.50 Hz, 2H) 5.23 (s, 2 H) 5.92 (d, J = 3.08 Hz, 1 H) 6.96 (t, J = 5.61 Hz, 1 H)7.17 (d, J = 2.86 Hz, 1 H) 7.27 (d, J = 7.92 Hz, 1 H) 7.55 (dd, J =8.03, 1.65 Hz, 1 H) 8.26-8.42 (m, 1 H) D, 0.64 313 203

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.54 (s, 3 H) 4.72 (d, J = 5.72 Hz, 2 H)5.30 (s, 2 H) 5.59 (s, 2 H) 5.98 (d, J = 3.08 Hz, 1 H) 7.30-7.35 (m, 2H) 7.45 (t, J = 4.95 Hz, 1 H) 8.75 (d, J = 4.84 Hz, 2 H) D, 0.48 338 204

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.54 (s, 3 H) 4.71 (d, J = 5.72 Hz, 2 H)5.33 (s, 2 H) 5.63 (s, 2 H) 6.02 (d, J = 3.08 Hz, 1 H) 7.22-7.30 (m, 1H) 7.41 (d, J = 3.08 Hz, 1 H) 8.43 (s, 1 H) 8.52 (dd, J = 2.42, 1.54 Hz,1 H) 8.56 (d, J = 2.42 Hz, 1 H) E, 0.92 338 205

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.57 (s, 3 H) 3.80 (s, 3 H) 4.85 (d, J =5.72 Hz, 2 H) 5.56 (s, 2 H) 6.24 (d, J = 2.86 Hz, 1 H) 6.84-6.90 (m, 2H) 7.03 (d, J = 8.14 Hz, 1 H) 7.28-7.34 (m, 1 H) 7.40 (d, J = 2.86 Hz, 1H) 7.49 (br. s., 2 H) 8.22-8.28 (m, 1 H) 12.89 (br. s., 1 H) E, 1.31 366206

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21 (d, J = 6.6 Hz, 3 H), 2.65 (s, 3H), 3.27 (s, 3 H), 3.32-3.35 (m, 1 H), 3.47 (dd, J = 9.2, 5.1 Hz, 1 H),4.35-4.55 (m, 6 1 H), 5.25 (s, 2 H), 5.36 (d, J = 4.8 Hz, 2 H), 5.92 (d,J = 3.1 Hz, 1 H), 6.76 (d, J = 7.5 Hz, 1 H), 7.30 (d, J = 3.1 Hz, 1 H),7.40 (s, 1 H) E, 1.33 333 207

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.37 (s, 3 H) 4.97 (d, J = 5.06 Hz, 2 H)5.81 (s, 2 H) 6.31 (d, J = 2.86 Hz, 1 H) 7.37 (d, J = 7.70 Hz, 1 H) 7.43(s, 1 H) 7.47-7.52 (m, 1 H) 7.57 (br. s., 1 H) 7.75 (d, J = 3.08 Hz, 1H) 7.97 (t, J = 7.70 Hz, 1 H) 8.53 (d, J = 4.62 Hz, 1 H) 9.50 (br. s., 1H) 12.88 (br. s., 1 H) E, 1.21 352 208

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.37 (s, 3 H) 4.72 (s, 2 H) 4.82 (d, J =5.72 Hz, 2 H) 5.29 (s, 2 H) 5.46 (s, 2 H) 5.96-6.00 (m, 1 H) 7.29-7.37(m, 2 H) 7.42 (d, J = 3.08 Hz, 1 H) 7.81 (td, J = 8.00, 1.50 Hz, 1 H)8.12 (t, J = 6.16 Hz, 1 H) 8.45-8.50 (m, 1 H) E, 1.15 367 209

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.49 (s, 3 H) 3.71 (s, 6 H) 4.70 (d, J =5.72 Hz, 2 H) 5.27 (s, 2 H) 5.41 (s, 2 H) 5.98 (d, J = 2.86 Hz, 1 H)6.11 (s, 1 H) 6.79 (t, J = 5.61 Hz, 1 H) 7.28 (d, J = 2.86 Hz, 1 H) E,1.23 398 210

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.19 (d, J = 1.10 Hz, 3 H) 3.68 (s, 6 H)4.77 (d, J = 5.72 Hz, 2 H) 5.68 (s, 2 H) 6.12 (s, 1 H) 6.28 (d, J = 3.08Hz, 1 H) 6.70 (d, J = 1.32 Hz, 1 H) 7.45 (br. s., 1 H) 7.59 (d, J = 3.08Hz, 1 H) 8.12 (t, J = 5.50 Hz, 1 H) 12.59-12.72 (m, 1 H) E, 1.27 397 211

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (d, J = 6.60 Hz, 3 H) 3.23-3.30 (m,4 H) 3.43 (dd, J = 9.02, 5.06 Hz, 1 H) 4.36-4.44 (m, 1 H) 5.27 (br. s.,2 H) 5.36-5.47 (m, 2 H) 5.95 (d, J = 2.64 Hz, 1 H) 7.19 (d, J = 7.04 Hz,1 H) 7.33-7.43 (m, 3 H) 7.85 (t, J = 7.37 Hz, 1 H) 8.55 (d, J = 3.96 Hz,1 H) E, 1.21 313 212

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (d, J = 6.60 Hz, 3 H) 3.25 (s, 3 H)3.29 (s, 3 H) 3.32-3.35 (m, 1 H) 3.45 (dd, J = 9.35, 5.17 Hz, 1 H) 3.61(t, J = 4.73 Hz, 2 H) 4.28-4.39 (m, 2 H) 4.44 (dt, J = 12.71, 6.30 Hz, 1H) 5.32 (br. s., 2 H) 5.93 (br. s., 1 H) 6.24 (d, J = 7.70 Hz, 1 H) 7.16(s, 1 H) E, 1.21 280 213

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.25 (d, J = 1.10 Hz, 3 H) 3.89 (s, 3 H)4.76 (d, J = 5.50 Hz, 2 H) 5.29 (s, 2 H) 5.40 (s, 2 H) 5.93 (d, J = 3.08Hz, 1 H) 6.76 (d, J = 1.10 Hz, 1 H) 7.25 (d, J = 3.08 Hz, 1 H) 7.39 (dd,J = 8.36, 4.62 Hz, 1 H) 7.53 (dd, J = 8.36, 1.10 Hz, 1 H) 7.94 (dd, J =4.73, 1.21 Hz, 1 H) 8.36 (t, J = 5.61 Hz, 1 H) E, 1.29 366 214

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.05 (d, J = 1.32 Hz, 3 H) 4.73 (d, J =5.72 Hz, 2 H) 5.31 (s, 2 H) 5.47 (s, 2 H) 5.98 (d, J = 3.08 Hz, 1 H)7.29-7.35 (m, 2 H) 7.42 (d, J = 3.08 Hz, 1 H) 7.67 (d, J = 1.10 Hz, 1 H)7.81 (td, J = 7.70, 1.76 Hz, 1 H) 7.99 (t, J = 5.61 Hz, 1 H) 8.41-8.45(m, 1 H) E, 1.17 336 215

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.31 (s, 3 H) 3.80 (s, 3 H) 4.77 (d, J =5.72 Hz, 2 H) 5.34 (s, 2 H) 5.43 (s, 2 H) 6.01 (d, J = 2.86 Hz, 1 H)6.46-6.50 (m, 1 H) 6.80 (t, J = 7.26 Hz, 1 H) 6.90 (t, J = 5.83 Hz, 1 H)7.00 (d, J = 8.14 Hz, 1 H) 7.20-7.27 (m, 2 H) 7.31 (d, J = 1.10 Hz, 1 H)E, 1.42 381 216

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.43 (s, 3 H) 4.85 (d, J = 5.72 Hz, 2 H)5.33 (s, 2 H) 5.49 (s, 2 H) 5.99 (d, J = 3.08 Hz, 1 H) 7.24 (d, J = 7.70Hz, 1 H) 7.34 (ddd, J = 7.54, 4.90, 0.99 Hz, 1 H) 7.43 (d, J = 3.08 Hz,1 H) 7.80 (td, J = 7.70, 1.76 Hz, 1 H) 8.03 (t, J = 5.61 Hz, 1 H)8.44-8.47 (m, 1 H) E, 0.98 337 Compounds were prepared according to themethods described in the experimental section. *^(R) indicates a pureenantiomer of unknown configuration, drawn in R configuration. *^(S)indicates a pure enantiomer of unknown configuration, drawn in Sconfiguration.Analytical Methods.

All compounds were characterized by LC-MS according to the followingLC-MS methods.

Method A.

Using a Phenomenex Kinetex column (XB-C18, 50×4.6 mm I.D. 2.6 μm) heldat 35° C. MS detection: API-ES positive ionization mode, mass range100-1200. PDA detection (λ=190-400 nm). The following gradient was usedwith a 2 μL injection:

Solvent A H₂O + 0.1% Formic Acid Solvent B Acetonitrile Time (min) % A %B Flow (mL/min) 0.0 95 5 3.0 4.2 5 95 3.0 4.9 5 95 3.0 5.0 95 5 3.0Method B.

Reversed phase UPLC (Ultra Performance Liquid Chromatography) wascarried out on a bridged ethylsiloxane/silica hybrid (BEH) C18 column(1.7 μm, 2.1×50 mm; Waters Acquity) with a flow rate of 0.8 ml/min. Twomobile phases (10 mM ammonium acetate in H₂O/acetonitrile 95/5; mobilephase B: acetonitrile) were used to run a gradient condition from 95% Aand 5% B to 5% A and 95% B in 1.3 minutes and hold for 0.7 minutes. Aninjection volume of 0.75 μl was used. Cone voltage was 30 V for positiveionization mode and 30 V for negative ionization mode.

Method C.

Analyses were carried out on a Waters XTerra C18 column (100×4.6 mm I.D.3.5 μm particles) at 40° C., with a flow rate of 1.6 mL/min. A gradientelution was performed as follows: from 100% of a solution of ammoniumacetate (25 mM) in Water/Acetonitrile 90:10 to a mixture ofAcetonitrile/Methanol 50:50 in 7.5 min; from the resulting compositionto 100% Acetonitrile in 1.0 min; 100% Acetonitrile for 1.5 min; from100% Acetonitrile to 100% to 100% of a solution of ammonium acetate (25mM) in Water/Acetonitrile 90:10 (25 mM) in 3.0 minutes. The standardinjection volume was 3 μL. Acquisition ranges were set to 200-400 nm forthe UV.

Method D.

The LC measurement was performed using an Acquity UPLC (Waters) systemcomprising a binary pump, a sample organizer, a column heater (set at55° C.), a diode-array detector (DAD) and a column as specified in therespective methods below. Flow from the column was split to a MSspectrometer. The MS detector was configured with an electrosprayionization source. Mass spectra were acquired by scanning from 100 to1000 in 0.18 seconds using a dwell time of 0.02 seconds. The capillaryneedle voltage was 3.5 kV and the source temperature was maintained at140° C. Nitrogen was used as the nebulizer gas. Reversed phase UPLC(Ultra Performance Liquid Chromatography) was carried out on a bridgedethylsiloxane/silica hybrid (BEH) C18 column (1.7 μm, 2.1×50 mm; WatersAcquity) with a flow rate of 0.8 mL/min. Two mobile phases (10 mMammonium acetate in H₂O/acetonitrile 95/5; mobile phase B: acetonitrile)were used to run a gradient condition from 95% A and 5% B to 5% A and95% B in 1.3 minutes and hold for 0.3 minutes. An injection volume of0.5 μl was used. Cone voltage was 10 V for positive ionization mode and20 V for negative ionization mode.

Method E

Flow Col Run Instrument Column Mobile phase Gradient Temp time Waters:Waters: A: 10 mM From 100% A 0.8 3.5 Acquity ® HSS T3 CH₃COONH₄ to 5% Ain 2.10 55 UPLC ® - (1.8 μm, in 95% H2O + min, to 0% A DAD and 2.1*1005% CH₃CN in 0.90 min, to SQD mm) B: CH₃CN 5% A in 0.5 minMethod F

Flow Mobile Col Run Instrument Column phase Gradient Temp time Waters:Waters: A: 25 mM From 100% A 1.6 11 Alliance ®- Xterra CH₃COONH₄ to 1%A, 49% 40 DAD - ZQ MS C18 in 95% H2O + B and 50% C and ELSD (3.5 5%CH₃CN, in 6.5 min, 2000 Alltech μm, B: CH₃CN, to 1% A and 4.6*100 C:CH3OH, D: 99% B in 0.5 mm) (40% CH3CN min, to 100% and 40% CH3OH D in 1min held and 20% H2O for 1.0 min to with 0.25% 100% A in 0.5 CH3COOH minand held for 1.5 min.Biological Activity of Compounds of Formula (I)Description of Biological AssaysAssessment of TLR7 and TLR8 Activity

The ability of compounds to activate human TLR7 and/or TLR8 was assessedin a cellular reporter assay using HEK293 cells transiently transfectedwith a TLR7 or TLR8 expression vector and NFκB-luc reporter construct.

Briefly, HEK293 cells were grown in culture medium (DMEM supplementedwith 10% FCS and 2 mM Glutamine). For transfection of cells in 10 cmdishes, cells were detached with Trypsin-EDTA, transfected with a mix ofCMV-TLR7 or TLR8 plasmid (750 ng), NFκB-luc plasmid (375 ng) and atransfection reagent and incubated overnight at 37° C. in a humidified5% CO₂ atmosphere. Transfected cells were then detached withTrypsin-EDTA, washed in PBS and resuspended in medium to a density of1.67×10⁵ cells/mL. Thirty microliters of cells were then dispensed intoeach well in 384-well plates, where 10 μL of compound in 4% DMSO wasalready present. Following 6 hours incubation at 37° C., 5% CO₂, theluciferase activity was determined by adding 15 μL of Steady Lite Plussubstrate (Perkin Elmer) to each well and readout performed on a ViewLuxultraHTS microplate imager (Perkin Elmer). Dose response curves weregenerated from measurements performed in quadruplicates. Lowesteffective concentrations (LEC) values, defined as the concentration thatinduces an effect which is at least two fold above the standarddeviation of the assay, were determined for each compound.

Compound toxicity was determined in parallel using a similar dilutionseries of compound with 30 μL per well of cells transfected with theCMV-TLR7 construct alone (1.67×10⁵ cells/mL), in 384-well plates. Cellviability was measured after 6 hours incubation at 37° C., 5% CO₂ byadding 15 μL of ATP lite (Perkin Elmer) per well and reading on aViewLux ultraHTS microplate imager (Perkin Elmer). Data was reported asCC₅₀.

In parallel, a similar dilution series of compound was used (10 μL ofcompound in 4% DMSO) with 30 μL per well of cells transfected withNFκB-luc reporter construct alone (1.67×10⁵ cells/mL). Six hours afterincubation at 37° C., 5% CO₂, the luciferase activity was determined byadding 15 μl of Steady Lite Plus substrate (Perkin Elmer) to each welland readout performed on a ViewLux ultraHTS microplate imager (PerkinElmer). Counterscreen data is reported as LEC.

Activation of ISRE Promoter Elements

The potential of compounds to induce IFN-I was also evaluated bymeasuring the activation of interferon-stimulated responsive elements(ISRE) by conditioned media from PBMC. The ISRE element of sequenceGAAACTGAAACT is highly responsive to the STAT1-STAT2-IRF9 transcriptionfactor, activated upon binding of IFN-I to their receptor IFNAR(Clontech, PT3372-5W). The plasmid pISRE-Luc from Clontech (ref. 631913)contains 5 copies of this ISRE element, followed by the fireflyluciferase ORF. A HEK293 cell line stably transfected with pISRE-Luc(HEK-ISREluc) was established to profile of the conditioned PBMC cellculture media.

Briefly, PBMCs were prepared from buffy coats of at least two donorsusing a standard Ficoll centrifugation protocol. Isolated PBMCs wereresuspended in RPMI medium supplemented with 10% human AB serum and2×10⁵ cells/well were dispensed into 384-well plates containingcompounds (70 μL total volume). After overnight incubation, 10 μL ofsupernatant was transferred to 384-well plates containing 5×10³HEK-ISREluc cells/well in 30 μL (plated the day before). Following 24hours of incubation, activation of the ISRE elements was measured byassaying luciferase activity using 40 μL/well Steady Lite Plus substrate(Perkin Elmer) and measured with ViewLux ultraHTS microplate imager(Perkin Elmer). The stimulating activity of each compound on theHEK-ISREluc cells was reported as LEC value, defined as the compoundconcentration applied to the PBMCs resulting in a luciferase activity atleast two fold above the standard deviation of the assay. The LEC inturn indicates the degree of ISRE activation on transfer of a definedamount of PBMC culture medium. Recombinant interferon α-2a (Roferon-A)was used as a standard control compound.

TABLE 2 Activity of compounds of formula (I). All compounds showed noactivity (LEC >25 μM) in the HEK 293 NF-kB counterscreen assay describedabove. TLR7 TLR8 PBMC LEC LEC LEC # STRUCTURE (μM) (μM) (μM) 1

0.20 >25 0.20 2

0.50 >25 0.60 3

2.6 >25 1.2 4

0.60 13.5 0.4 5

0.30 >25 0.2 6

1.3 >25 0.7 7

0.61 >25 0.8 8

0.49 1.7 0.15 9

0.53 2.1 0.22 10

0.15 >25 0.06 11

1.5 3.5 0.56 12

0.14 0.7 0.05 13

0.80 >25 0.89 14

0.52 6.57 0.01 15

5.84 >25 0.1 16

0.89 >25 0.6 17

0.07 12.5 0.01 18

0.07 >25 0.01 19

2.5 7.06 0.62 20

0.14 1.3 0.02 21

0.009 7.4 0.0007 22

0.48 9.2 0.02 23

0.83 >25 0.27 24

0.02 6.47 0.0007 25

0.01 2.84 0.001 26

0.03 1.95 0.002 27

0.15 0.85 0.17 28

0.11 1.1 0.03 29

0.15 >25 0.04 30

0.16 0.67 0.05 31

0.22 >25 0.16 32

0.91 >25 0.52 33

0.03 >25 0.04 34

0.91 >25 0.54 35

1.49 >25 0.70 36

1.06 >25 0.59 37

0.005 >25 0.007 38

0.54 >25 0.63 39

0.17 >25 0.009 40

0.12 24.61 0.004 41

0.09 >25 0.11 42

0.28 >25 0.16 43

0.11 >25 0.17 44

1.51 >25 2.45 45

19.9 >25 0.74 46

0.83 >25 0.17 47

17.5 >25 1.79 48

0.05 >25 0.03 49

22.43 >25 2.34 50

1.01 >25 0.13 51

5.14 >25 0.59 52

0.12 >25 0.09 53

0.38 2.78 0.07 54

1.68 >25 0.90 55

0.08 0.81 0.06 56

0.99 17.5 0.07 57

0.33 >25 0.28 58

0.24 >25 0.90 59

0.37 >25 0.22 60

0.39 >25 0.33 61

1.01 >25 1.95 62

0.06 0.9934 0.06 63

0.67 >25 0.18 64

1.36 >25 0.26 65

0.1687 >25 0.08 66

2.57 3.96 0.91 67

0.056 6.71 0.04 68

0.19 >25 0.04 69

0.004 0.71 0.002 70

1.53 >25 0.75 71

0.32 4.68 0.24 72

0.13 >25 0.04 73

0.28 >25 0.13 74

0.10 >25 0.04 75

0.04 >25 0.04 76

0.01 4.09 0.007 77

0.008 2.62 0.002 78

0.0004 0.5577 <0.0004 79

0.004 0.94 0.001 80

<0.0006 0.689 <0.0004 81

0.01 22.02 0.002 82

0.07 0.57 0.01 83

1.57 >25 2.3 84

0.04 1.14 0.01 85

0.03 10.14 0.002 86

1.63 >25 0.47 87

0.01 >25 0.008 88

0.01 2.46 0.0006 89

0.04 >25 0.006 90

0.03 >25 0.01 91

0.05 2.17 0.02 92

0.10 4.46 0.02 93

0.26 >25 0.12 94

0.01 >25 0.01 95

0.01 3.26 0.007 96

0.05 >25 0.04 97

<0.01 0.23 0.001 98

<0.01 0.22 0.001 99

<0.01 0.1 <0.001 100

<0.01 0.04 <0.001 101

<0.01 0.08 <0.001 102

<0.01 0.14 <0.001 103

0.032 >25 0.018 104

11.960 >25 1.980 105

0.827 >25 0.194 106

0.008 0.59 0.005 107

2.030 >25 2.130 108

0.126 >25 0.070 109

0.005 7.17 0.003 110

0.002 >25 0.001 111

0.637 >25 0.293 112

0.741 >25 0.209 113

1.320 >25 0.807 114

0.186 2.27 0.133 115

0.241 7.93 0.079 116

0.049 >25 0.022 117

2.950 >22.7 1.430 118

1.650 >25 3.010 119

1.810 >25 2.180 120

3.220 >25 2.160 121

0.172 >25 0.046 122

0.050 >25 0.030 123

0.026 >25 0.002 124

0.003 >22 0.001 125

0.086 >25 0.009 126

0.054 >25 0.008 127

0.337 >25 0.019 128

0.342 >25 0.062 129

0.670 >25 0.122 130

1.940 >25 0.804 131

0.004 24.6 0.001 132

5.99 >25 0.879 133

0.07 >25 0.023 134

1.20 >25 0.104 135

12.5 >25 4.050 136

3.04 >25 0.559 137

13.8 >25 2.030 138

4.45 >25 0.502 139

1.41 >25 0.588 140

1.24 >25 0.513 141

0.43 >25 0.048 142

0.52 >25 0.134 143

0.10 >25 0.016 144

0.07 >25 0.009 145

0.05 >25 0.021 146

0.20 >25 0.139 147

4.49 >25 2.020 148

0.16 3.93 0.056 149

0.02 >25 0.006 150

0.25 >25 0.054 151

12.8 >25 2.580 152

0.73 >25 0.142 153

0.05 >25 0.002 154

0.08 >25 0.017 155

0.90 >25 0.415 156

0.05 >25 0.040 157

0.03 >25 0.003 158

0.05 >25 0.020 159

0.05 >25 0.019 160

8.07 >25 1.810 161

0.02 >25 0.009 162

0.32 >25 0.128 163

<0.01 0.75 0.001 164

0.04 15.93 0.025 165

4.94 >25 0.957 166

4.88 NA NA 167

0.09 >25 0.008 168

0.09 >25 0.011 169

0.04 >25 0.011 170

0.01 >25 0.002 171

0.02 >25 NA 172

1.40 >25 0.017 173

0.53 >25 0.066 174

6.13 >25 2.200 175

0.02 >25 0.009 176

0.04 >25 0.009 177

8.67 >25 3.930 178

0.15 >25 0.014 179

0.02 >25 0.003 180

0.01 >25 0.004 181

0.06 20.2 0.015 182

0.05 >25 0.018 183

0.59 >25 0.009 184

0.49 >25 0.131 185

0.07 >25 0.018 186

0.14 >25 0.035 187

4.78 >25 0.520 188

7.62 >25 0.047 189

0.40 >25 0.074 190

0.26 >25 0.038 191

0.06 >24 0.006 192

0.07 >25 0.030 193

11.3 >25 0.447 194

2.38 >25 0.507 195

0.16 >25 0.024 196

0.01 12.6 0.002 197

0.39 >25 0.040 198

8.76 >25 0.617 199

0.60 23.5 0.032 200

0.17 11.4 0.035 201

7.30 >25 0.978 202

1.61 >25 0.580 203

1.04 >25 0.138 204

1.78 >25 0.188 205

<0.01 7.7 0.001 206

0.74 15 0.129 207

0.06 23 0.009 208

5.14 >25 0.402 209

0.04 >25 0.008 210

0.02 >25 0.003 211

6.94 22 0.470 212

7.60 >25 2.090 213

<0.01 >25 0.001 214

1.16 >25 0.151 215

<0.01 >25 0.001 216

1.24 >25 0.091

The invention claimed is:
 1. A compound of formula (I)

a pharmaceutically acceptable salt or solvate thereof wherein; R₁ is H,fluorine or methyl; R₂ is H, halogen or C₁₋₃ alkyl; R₃ is C₁₋₆ alkyloptionally substituted by aryl wherein said aryl isoptionally-substituted by one or more substituents independentlyselected from the group consisting of aryloxy, halogen, aryl,alkylamino, dialkylamino, C₁₋₆ alkyl, —CO₂H, —C(O)OC₁₋₆ alkyl, —CONH₂,—CN, and C₁₋₆ alkoxy; or R₃ is C₁₋₆ alkyl optionally substituted by C₁₋₆alkene, C₃₋₇ cycloalkyl or C₃₋₇ heterocycloalkyl; or R₃ is C₁₋₆ alkyloptionally substituted by C₁₋₆ alkoxy wherein said C₁₋₆ alkoxy isoptionally substituted by aryl; and R₄ is C₁₋₈ alkyl optionallysubstituted by one or more substituents independently selected from thegroup consisting of hydroxyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₃₋₇ cycloalkyl,C₂₋₆ alkenyl, aryl, heteroaryl, and C₃₋₇ cycloalkyl wherein saidheteroaryl and said C₃₋₇ cycloalkyl are optionally substituted by C₁₋₆alkyl; with the proviso that 2-amino,4-(N-butylamino)-5-(alphamethylbenzyl)pyrrolo[3,2-d] pyrimidine isexcluded.
 2. A compound as claimed in claim 1, wherein R₃ is methyloptionally substituted by aryl.
 3. A compound as claimed in claim 1,wherein each of R₃ and R₄ is independently C₁₋₃ alkyl substituted byaryl.
 4. A compound as claimed in claim 1, wherein R₁ is fluorine and R₂is hydrogen.
 5. A pharmaceutical composition comprising a compound asclaimed in claim 1 together with one or more pharmaceutically acceptableexcipients, diluents or carriers.
 6. A compound as claimed in claim 1,wherein R₃ is aryl-substituted C₁₋₃ alkyl and the aryl in saidaryl-substituted C₁₋₃ alkyl is optionally substituted by one or moresubstituents independently selected from the group consisting ofaryloxy, halogen, aryl, alkylamino, dialkylamino, C₁₋₆ alkyl, —CO₂H,C(O)OC₁₋₆ alkyl, —CONH₂, —CN, and C₁₋₆ alkoxy; and R₄ isaryl-substituted C₁₋₃ alkyl.